The explosion of interest in interventional psychiatry is highlighted by 2 recent reviews published in Current Psychiatry.^1,2 While this is clearly desirable, the rate of growth has created problems. Expansion of interventional modalities has outpaced the training and education of our residents and practicing psychiatrists.

Psychiatry’s failure to address these changes would be a dire error, as psychiatrists could lose control of our field’s advances and growth. But this creates an even larger question: what are the next steps we need to take? We believe interventional psychiatry must be recognized as its own psychiatric subspeciality, receive greater emphasis in psychiatry residency training, and be subject to standardization by professional organizations.

Psychiatry has incorporated procedures into patient care for almost 100 years, starting with electroconvulsive therapy (ECT) and insulin shock therapy in the 1930s.^3,4 However, in the last 10 years, the rapid expansion of FDA approvals of neuromodulation procedures to treat psychiatric conditions (including vagus nerve stimulation in 2005, transcranial magnetic stimulation [TMS] in 2008, and the device exception granted for the use of deep brain stimulation in 2009) has produced the moniker “interventional psychiatry” for this unofficial psychiatric subspeciality.^5,6

If we are to establish interventional psychiatry as a recognized subspeciality, it is important to create a universally accepted definition. We propose the term refer to therapeutic techniques or processes that may or may not be invasive but require special training to perform. Additionally, interventional psychiatry should include even minimally invasive procedures, such as ketamine infusions, medication implants, long-acting injectable (LAI) medications, and processes that require a Risk Evaluation and Mitigation Strategy (REMS), such as those utilized with clozapine, esketamine, or olanzapine for extended-release injectable suspension⁷ (see “Risk Evaluation and Mitigation Strategy programs: How they can be improved”). The proportions of clinicians who prescribe clozapine (7%)⁸ or LAIs (32.1% to 77.7%, depending on the patient population being treated)^9,10 is evidence that the interventional nature of these treatments creates obstacles to their use.

This vacuum of adequate training among psychiatrists has caused interventional psychiatry to grow beyond the confines of the psychiatric field. In most metropolitan areas of the United States, there are clinicians who focus on a specific interventional treatment, such as ketamine infusions or TMS administration. The creation of these specialized clinics has frequently been pioneered by nonpsychiatrists, such as anesthesiologists. This may be attributed to these clinicians’ level of comfort with procedures, or because they possess an infrastructure within their practice that facilitates delivery of the services. In certain states with independent-practice laws, midlevel clinicians are granted permission to open these clinics. However, having nonpsychiatrists provide these treatments to patients with complex psychiatric disorders without psychiatrist involvement makes it less likely that the appropriateness of treatment will be determined, or that the treatment will be incorporated into the patient’s overall biopsychosocial treatment plan.

A gap in training

There is evidence the growth of interventional psychiatry has exceeded the capacity of the current training infrastructure to provide trainees with adequate exposure to these procedures. The Accreditation Council for Graduate Medical Education requires that psychiatry residents be trained in the indications for and use of ECT and neuromodulation therapies but does not provide any specifics about how this training should occur,¹¹ and the Psychiatry Milestones do not indicate how competency in these therapies can be achieved.¹² Most trainees have exposure to some interventional treatments, such as ECT or clozapine administration, during residency. However, in 1 survey, only 63% of residents had prescribed clozapine, and 83% indicated they wanted additional experience.¹³ In a survey of 91 training programs, 75% stated that ECT was required of residents, but 37% estimated that a typical resident would participate in <10 treatments.¹⁴ Even more surprising, 27% estimated that the typical resident would care for <5 patients receiving ECT.¹⁴

Addressing the changing role of interventional practices in our field must occur on multiple levels, starting with a core curriculum during residency training, expanded learning opportunities for residents with a specific interest in interventional psychiatry, and, most important, a formal interventional psychiatry fellowship leading to certification from the American Board of Medical Specialties.^5,6 There are growing numbers of 1-year fellowship programs that offer extensive experiences in neuromodulation and novel pharma­cologic treatment and may produce the next generation of leaders in this field. However, training in interventional psychiatry techniques for practicing psychiatrists wishing to expand their treatment offerings is generally quite limited.

Oversight of interventional psychiatry training should be performed by peers. Therefore, creation of an interventional psychiatry society, or a work group within a larger organization, is necessary. While much of this already exists, it is fragmented into associations focused on unique aspects of interventional psychiatry, such as just ECT (eg, International Society for ECT and Neurostimulation), just TMS (eg, Clinical TMS Society), or just ketamine (eg, the American Society of Ketamine Physicians). Despite disparate foci, the goal would be for all to unite into a parent interventional organization that can face these challenges. These organizations have already united a core of individual interventional psychiatrists who can lead psychiatry into the future. They can provide input into guidelines, minimal standards, procedures, protocols, and outcome measures. They also can address any ethical issues that may arise with the use of more invasive treatments.

Change, especially the monumental changes in practice that accompany interventional psychiatry, is both exciting and intimidating. However, certain “growing pains” along the way require urgent consideration. Ultimately, as a field, we either adapt to change or get left behind.

The explosion of interest in interventional psychiatry is highlighted by 2 recent reviews published in Current Psychiatry.^1,2 While this is clearly desirable, the rate of growth has created problems. Expansion of interventional modalities has outpaced the training and education of our residents and practicing psychiatrists.

Psychiatry’s failure to address these changes would be a dire error, as psychiatrists could lose control of our field’s advances and growth. But this creates an even larger question: what are the next steps we need to take? We believe interventional psychiatry must be recognized as its own psychiatric subspeciality, receive greater emphasis in psychiatry residency training, and be subject to standardization by professional organizations.

Psychiatry has incorporated procedures into patient care for almost 100 years, starting with electroconvulsive therapy (ECT) and insulin shock therapy in the 1930s.^3,4 However, in the last 10 years, the rapid expansion of FDA approvals of neuromodulation procedures to treat psychiatric conditions (including vagus nerve stimulation in 2005, transcranial magnetic stimulation [TMS] in 2008, and the device exception granted for the use of deep brain stimulation in 2009) has produced the moniker “interventional psychiatry” for this unofficial psychiatric subspeciality.^5,6

If we are to establish interventional psychiatry as a recognized subspeciality, it is important to create a universally accepted definition. We propose the term refer to therapeutic techniques or processes that may or may not be invasive but require special training to perform. Additionally, interventional psychiatry should include even minimally invasive procedures, such as ketamine infusions, medication implants, long-acting injectable (LAI) medications, and processes that require a Risk Evaluation and Mitigation Strategy (REMS), such as those utilized with clozapine, esketamine, or olanzapine for extended-release injectable suspension⁷ (see “Risk Evaluation and Mitigation Strategy programs: How they can be improved”). The proportions of clinicians who prescribe clozapine (7%)⁸ or LAIs (32.1% to 77.7%, depending on the patient population being treated)^9,10 is evidence that the interventional nature of these treatments creates obstacles to their use.

This vacuum of adequate training among psychiatrists has caused interventional psychiatry to grow beyond the confines of the psychiatric field. In most metropolitan areas of the United States, there are clinicians who focus on a specific interventional treatment, such as ketamine infusions or TMS administration. The creation of these specialized clinics has frequently been pioneered by nonpsychiatrists, such as anesthesiologists. This may be attributed to these clinicians’ level of comfort with procedures, or because they possess an infrastructure within their practice that facilitates delivery of the services. In certain states with independent-practice laws, midlevel clinicians are granted permission to open these clinics. However, having nonpsychiatrists provide these treatments to patients with complex psychiatric disorders without psychiatrist involvement makes it less likely that the appropriateness of treatment will be determined, or that the treatment will be incorporated into the patient’s overall biopsychosocial treatment plan.

A gap in training

There is evidence the growth of interventional psychiatry has exceeded the capacity of the current training infrastructure to provide trainees with adequate exposure to these procedures. The Accreditation Council for Graduate Medical Education requires that psychiatry residents be trained in the indications for and use of ECT and neuromodulation therapies but does not provide any specifics about how this training should occur,¹¹ and the Psychiatry Milestones do not indicate how competency in these therapies can be achieved.¹² Most trainees have exposure to some interventional treatments, such as ECT or clozapine administration, during residency. However, in 1 survey, only 63% of residents had prescribed clozapine, and 83% indicated they wanted additional experience.¹³ In a survey of 91 training programs, 75% stated that ECT was required of residents, but 37% estimated that a typical resident would participate in <10 treatments.¹⁴ Even more surprising, 27% estimated that the typical resident would care for <5 patients receiving ECT.¹⁴

Addressing the changing role of interventional practices in our field must occur on multiple levels, starting with a core curriculum during residency training, expanded learning opportunities for residents with a specific interest in interventional psychiatry, and, most important, a formal interventional psychiatry fellowship leading to certification from the American Board of Medical Specialties.^5,6 There are growing numbers of 1-year fellowship programs that offer extensive experiences in neuromodulation and novel pharma­cologic treatment and may produce the next generation of leaders in this field. However, training in interventional psychiatry techniques for practicing psychiatrists wishing to expand their treatment offerings is generally quite limited.

Oversight of interventional psychiatry training should be performed by peers. Therefore, creation of an interventional psychiatry society, or a work group within a larger organization, is necessary. While much of this already exists, it is fragmented into associations focused on unique aspects of interventional psychiatry, such as just ECT (eg, International Society for ECT and Neurostimulation), just TMS (eg, Clinical TMS Society), or just ketamine (eg, the American Society of Ketamine Physicians). Despite disparate foci, the goal would be for all to unite into a parent interventional organization that can face these challenges. These organizations have already united a core of individual interventional psychiatrists who can lead psychiatry into the future. They can provide input into guidelines, minimal standards, procedures, protocols, and outcome measures. They also can address any ethical issues that may arise with the use of more invasive treatments.

Change, especially the monumental changes in practice that accompany interventional psychiatry, is both exciting and intimidating. However, certain “growing pains” along the way require urgent consideration. Ultimately, as a field, we either adapt to change or get left behind.

The explosion of interest in interventional psychiatry is highlighted by 2 recent reviews published in Current Psychiatry.^1,2 While this is clearly desirable, the rate of growth has created problems. Expansion of interventional modalities has outpaced the training and education of our residents and practicing psychiatrists.

Psychiatry’s failure to address these changes would be a dire error, as psychiatrists could lose control of our field’s advances and growth. But this creates an even larger question: what are the next steps we need to take? We believe interventional psychiatry must be recognized as its own psychiatric subspeciality, receive greater emphasis in psychiatry residency training, and be subject to standardization by professional organizations.

Psychiatry has incorporated procedures into patient care for almost 100 years, starting with electroconvulsive therapy (ECT) and insulin shock therapy in the 1930s.^3,4 However, in the last 10 years, the rapid expansion of FDA approvals of neuromodulation procedures to treat psychiatric conditions (including vagus nerve stimulation in 2005, transcranial magnetic stimulation [TMS] in 2008, and the device exception granted for the use of deep brain stimulation in 2009) has produced the moniker “interventional psychiatry” for this unofficial psychiatric subspeciality.^5,6

If we are to establish interventional psychiatry as a recognized subspeciality, it is important to create a universally accepted definition. We propose the term refer to therapeutic techniques or processes that may or may not be invasive but require special training to perform. Additionally, interventional psychiatry should include even minimally invasive procedures, such as ketamine infusions, medication implants, long-acting injectable (LAI) medications, and processes that require a Risk Evaluation and Mitigation Strategy (REMS), such as those utilized with clozapine, esketamine, or olanzapine for extended-release injectable suspension⁷ (see “Risk Evaluation and Mitigation Strategy programs: How they can be improved”). The proportions of clinicians who prescribe clozapine (7%)⁸ or LAIs (32.1% to 77.7%, depending on the patient population being treated)^9,10 is evidence that the interventional nature of these treatments creates obstacles to their use.

This vacuum of adequate training among psychiatrists has caused interventional psychiatry to grow beyond the confines of the psychiatric field. In most metropolitan areas of the United States, there are clinicians who focus on a specific interventional treatment, such as ketamine infusions or TMS administration. The creation of these specialized clinics has frequently been pioneered by nonpsychiatrists, such as anesthesiologists. This may be attributed to these clinicians’ level of comfort with procedures, or because they possess an infrastructure within their practice that facilitates delivery of the services. In certain states with independent-practice laws, midlevel clinicians are granted permission to open these clinics. However, having nonpsychiatrists provide these treatments to patients with complex psychiatric disorders without psychiatrist involvement makes it less likely that the appropriateness of treatment will be determined, or that the treatment will be incorporated into the patient’s overall biopsychosocial treatment plan.

A gap in training

There is evidence the growth of interventional psychiatry has exceeded the capacity of the current training infrastructure to provide trainees with adequate exposure to these procedures. The Accreditation Council for Graduate Medical Education requires that psychiatry residents be trained in the indications for and use of ECT and neuromodulation therapies but does not provide any specifics about how this training should occur,¹¹ and the Psychiatry Milestones do not indicate how competency in these therapies can be achieved.¹² Most trainees have exposure to some interventional treatments, such as ECT or clozapine administration, during residency. However, in 1 survey, only 63% of residents had prescribed clozapine, and 83% indicated they wanted additional experience.¹³ In a survey of 91 training programs, 75% stated that ECT was required of residents, but 37% estimated that a typical resident would participate in <10 treatments.¹⁴ Even more surprising, 27% estimated that the typical resident would care for <5 patients receiving ECT.¹⁴

Addressing the changing role of interventional practices in our field must occur on multiple levels, starting with a core curriculum during residency training, expanded learning opportunities for residents with a specific interest in interventional psychiatry, and, most important, a formal interventional psychiatry fellowship leading to certification from the American Board of Medical Specialties.^5,6 There are growing numbers of 1-year fellowship programs that offer extensive experiences in neuromodulation and novel pharma­cologic treatment and may produce the next generation of leaders in this field. However, training in interventional psychiatry techniques for practicing psychiatrists wishing to expand their treatment offerings is generally quite limited.

Oversight of interventional psychiatry training should be performed by peers. Therefore, creation of an interventional psychiatry society, or a work group within a larger organization, is necessary. While much of this already exists, it is fragmented into associations focused on unique aspects of interventional psychiatry, such as just ECT (eg, International Society for ECT and Neurostimulation), just TMS (eg, Clinical TMS Society), or just ketamine (eg, the American Society of Ketamine Physicians). Despite disparate foci, the goal would be for all to unite into a parent interventional organization that can face these challenges. These organizations have already united a core of individual interventional psychiatrists who can lead psychiatry into the future. They can provide input into guidelines, minimal standards, procedures, protocols, and outcome measures. They also can address any ethical issues that may arise with the use of more invasive treatments.

Change, especially the monumental changes in practice that accompany interventional psychiatry, is both exciting and intimidating. However, certain “growing pains” along the way require urgent consideration. Ultimately, as a field, we either adapt to change or get left behind.

In March 2020, as I was wheeling my patient into the operating room to perform a Caesarean section, covered head-to-toe in COVID personal protective equipment, my phone rang. It was Jody Schindelheim, MD, Director of the Psychiatry Residency Program at Tufts Medical Center in Boston, calling to offer me a PGY-2 spot in their program.

As COVID upended the world, I was struggling with my own major change. My path had been planned since before medical school: I would grind through a 4-year OB/GYN residency, complete a fellowship, and establish myself as a reproductive endocrinology and infertility specialist. My personal statement emphasized my dream that no woman should be made to feel useless based on infertility. OB/GYN, genetics, and ultrasound were my favorite rotations at the Albert Einstein College of Medicine in the Bronx.

However, 6 months into my OB/GYN intern year, I grew curious about the possibility of a future in reproductive psychiatry and women’s mental health. This decision was not easy. As someone who loved the adrenaline rush of delivering babies and performing surgery, I had paid little attention to psychiatry in medical school. However, my experience in gynecologic oncology in January 2020 made me realize my love of stories and trauma-informed care. I recall a woman, cachectic with only days left to live due to ovarian cancer, talking to me about her trauma and the power of her lifelong partner. Another woman, experiencing complications from chemotherapy to treat fallopian tube cancer, shared about her coping skill of chair yoga.

Fulfilling an unmet need

As I spent time with these 2 women and heard their stories, I felt compelled to help them with these psychological challenges. As a gynecologist, I addressed their physical needs, but not their personal needs. I spoke to many psychiatrists, including reproductive psychiatrists, in New York, who shared their stories and taught me about the prevalence of postpartum depression and psychosis. After caring for hundreds of pregnant and postpartum women in the Bronx, I thought about the unmet need for women’s mental health and how this career change could still fulfill my purpose of helping women feel empowered regardless of their fertility status.

In the inpatient and outpatient settings at Tufts, I have loved hearing my patients’ stories and providing continuity of care with medical management and therapy. My mentors in reproductive psychiatry inspired me to create the Reproductive Psychiatry Trainee Interest Group (https://www.repropsychtrainees.com), a national group for the burgeoning field that now has more than 650 members. With monthly lectures, journal clubs, and book clubs, I have surrounded myself with like-minded individuals who love learning about the perinatal, postpartum, and perimenopausal experiences.

As I prepare to begin a full-time faculty position in psychiatry at the University of Pennsylvania, I know I have found my joy and my calling. I once feared the life of a psychiatrist would be too sedentary for someone accustomed to the pace of OB/GYN. Now I know that my patients’ stories are all the motivation I need.

In March 2020, as I was wheeling my patient into the operating room to perform a Caesarean section, covered head-to-toe in COVID personal protective equipment, my phone rang. It was Jody Schindelheim, MD, Director of the Psychiatry Residency Program at Tufts Medical Center in Boston, calling to offer me a PGY-2 spot in their program.

As COVID upended the world, I was struggling with my own major change. My path had been planned since before medical school: I would grind through a 4-year OB/GYN residency, complete a fellowship, and establish myself as a reproductive endocrinology and infertility specialist. My personal statement emphasized my dream that no woman should be made to feel useless based on infertility. OB/GYN, genetics, and ultrasound were my favorite rotations at the Albert Einstein College of Medicine in the Bronx.

However, 6 months into my OB/GYN intern year, I grew curious about the possibility of a future in reproductive psychiatry and women’s mental health. This decision was not easy. As someone who loved the adrenaline rush of delivering babies and performing surgery, I had paid little attention to psychiatry in medical school. However, my experience in gynecologic oncology in January 2020 made me realize my love of stories and trauma-informed care. I recall a woman, cachectic with only days left to live due to ovarian cancer, talking to me about her trauma and the power of her lifelong partner. Another woman, experiencing complications from chemotherapy to treat fallopian tube cancer, shared about her coping skill of chair yoga.

Fulfilling an unmet need

As I spent time with these 2 women and heard their stories, I felt compelled to help them with these psychological challenges. As a gynecologist, I addressed their physical needs, but not their personal needs. I spoke to many psychiatrists, including reproductive psychiatrists, in New York, who shared their stories and taught me about the prevalence of postpartum depression and psychosis. After caring for hundreds of pregnant and postpartum women in the Bronx, I thought about the unmet need for women’s mental health and how this career change could still fulfill my purpose of helping women feel empowered regardless of their fertility status.

In the inpatient and outpatient settings at Tufts, I have loved hearing my patients’ stories and providing continuity of care with medical management and therapy. My mentors in reproductive psychiatry inspired me to create the Reproductive Psychiatry Trainee Interest Group (https://www.repropsychtrainees.com), a national group for the burgeoning field that now has more than 650 members. With monthly lectures, journal clubs, and book clubs, I have surrounded myself with like-minded individuals who love learning about the perinatal, postpartum, and perimenopausal experiences.

As I prepare to begin a full-time faculty position in psychiatry at the University of Pennsylvania, I know I have found my joy and my calling. I once feared the life of a psychiatrist would be too sedentary for someone accustomed to the pace of OB/GYN. Now I know that my patients’ stories are all the motivation I need.

In March 2020, as I was wheeling my patient into the operating room to perform a Caesarean section, covered head-to-toe in COVID personal protective equipment, my phone rang. It was Jody Schindelheim, MD, Director of the Psychiatry Residency Program at Tufts Medical Center in Boston, calling to offer me a PGY-2 spot in their program.

As COVID upended the world, I was struggling with my own major change. My path had been planned since before medical school: I would grind through a 4-year OB/GYN residency, complete a fellowship, and establish myself as a reproductive endocrinology and infertility specialist. My personal statement emphasized my dream that no woman should be made to feel useless based on infertility. OB/GYN, genetics, and ultrasound were my favorite rotations at the Albert Einstein College of Medicine in the Bronx.

However, 6 months into my OB/GYN intern year, I grew curious about the possibility of a future in reproductive psychiatry and women’s mental health. This decision was not easy. As someone who loved the adrenaline rush of delivering babies and performing surgery, I had paid little attention to psychiatry in medical school. However, my experience in gynecologic oncology in January 2020 made me realize my love of stories and trauma-informed care. I recall a woman, cachectic with only days left to live due to ovarian cancer, talking to me about her trauma and the power of her lifelong partner. Another woman, experiencing complications from chemotherapy to treat fallopian tube cancer, shared about her coping skill of chair yoga.

Fulfilling an unmet need

As I spent time with these 2 women and heard their stories, I felt compelled to help them with these psychological challenges. As a gynecologist, I addressed their physical needs, but not their personal needs. I spoke to many psychiatrists, including reproductive psychiatrists, in New York, who shared their stories and taught me about the prevalence of postpartum depression and psychosis. After caring for hundreds of pregnant and postpartum women in the Bronx, I thought about the unmet need for women’s mental health and how this career change could still fulfill my purpose of helping women feel empowered regardless of their fertility status.

In the inpatient and outpatient settings at Tufts, I have loved hearing my patients’ stories and providing continuity of care with medical management and therapy. My mentors in reproductive psychiatry inspired me to create the Reproductive Psychiatry Trainee Interest Group (https://www.repropsychtrainees.com), a national group for the burgeoning field that now has more than 650 members. With monthly lectures, journal clubs, and book clubs, I have surrounded myself with like-minded individuals who love learning about the perinatal, postpartum, and perimenopausal experiences.

As I prepare to begin a full-time faculty position in psychiatry at the University of Pennsylvania, I know I have found my joy and my calling. I once feared the life of a psychiatrist would be too sedentary for someone accustomed to the pace of OB/GYN. Now I know that my patients’ stories are all the motivation I need.

COVID-19’s increased demand on the mental health care delivery system led to expanded utilization of technology-based solutions, including digital tools to deliver care.¹ Technology-based solutions include both synchronous telehealth (eg, real-time interactive audio/video visits) and asynchronous tools such as smartphone applications (apps). Both real-time telehealth and apps continue to gain popularity. More than 10,000 mental health–related apps are available, and that number continues to rise.² Numerous web- or mobile-based apps are available to aid in the treatment of various psychiatric conditions, including generalized anxiety disorder (GAD), major depressive disorder, insomnia, and posttraumatic stress disorder (PTSD).

Clinicians may find it challenging to choose the best psychiatry-related apps to recommend to patients. This dilemma calls for an approach to help clinicians select apps that are safe and effective.² The American Psychiatric Association provides information to help mental health professionals navigate these issues and identify which aspects to consider when selecting an app for clinical use.³ The M-Health Index and Navigation Database also provides a set of objective evaluative criteria and offers guidance on choosing apps.⁴

In this article, we review 8 randomized controlled trials (RCTs) of mental health–related apps. We took several steps to ensure the RCTs we included were impactful and meaningful. First, we conducted a general search using mainstream search engines to assess which psychiatric apps were most popular for use in clinical practice. Using this list, we conducted a scholarly search engine query of RCTs using the name of the apps as a search parameter along with the following keywords: “mobile,” “web,” “applications,” and “psychiatry.” This search yielded approximately 50 results, which were narrowed down based on content and interest to a list of 8 articles (Table^5-12). These articles were then graded using the limitations of each study as the primary substrate for evaluation.

1. Linardon J, Shatte A, Rosato J, et al. Efficacy of a transdiagnostic cognitive-behavioral intervention for eating disorder psychopathology delivered through a smartphone app: a randomized controlled trial. Psychol Med. 2022;52(9):1679-1690. doi:10.1017/S0033291720003426

Many patients with eating disorders are unable to receive effective treatment due to problems with accessing health care. Smartphone apps may help bridge the treatment gap for patients in this position. Linardon et al⁵ developed an app that uses the principles of cognitive-behavioral therapy (CBT) for treating eating disorders and conducted this study to evaluate its effectiveness.

Study design

• This RCT assigned individuals who reported episodes of binge eating to a group that used a mobile app (n = 197) or to a waiting list (n = 195). At baseline, 42% of participants exhibited diagnostic-level symptoms of bulimia nervosa and 31% had symptoms of binge-eating disorder.
• Assessments took place at baseline, Week 4, and Week 8.
• The primary outcome was global levels of eating disorder psychopathology.
• Secondary outcomes were other eating disorder symptoms, impairment, and distress.

Outcomes

• Compared to the control group, participants who used the mobile app reported greater reductions in global eating disorder psychopathology (d = -0.80).
• Significant effects were also observed for secondary outcomes except compensatory behavior frequency.
• Overall, participants reported they were satisfied with the app.

Continue to: Conclusions/limitations

• Findings show this app could potentially be a cost-effective and easily accessible option for patients who cannot receive standard treatment for eating disorders.
• Limitations: The overall posttest attrition rate was 35%.

2. Christoforou M, Sáez Fonseca JA, Tsakanikos E. Two novel cognitive behavioral therapy–based mobile apps for agoraphobia: randomized controlled trial. J Med Internet Res. 2017;19(11):e398. doi:10.2196/jmir.7747

CBT is generally the most accepted first-line treatment for agoraphobia. However, numerous barriers to obtaining CBT can prevent successful treatment. Limited research has evaluated the efficacy of apps for treating agoraphobia. Christoforou et al⁶ conducted an RCT to determine the effectiveness of a self-guided smartphone app for improving agoraphobic symptoms, compared to a mobile app used to treat anxiety.

Study design

• Participants (N = 170) who self-identified as having agoraphobia were randomly assigned to use a smartphone app designed to target agoraphobia (Agoraphobia Free) or a smartphone app designed to help with symptoms of anxiety (Stress Free) for 12 weeks. Both apps were based on established cognitive behavioral principles.
• Assessment occurred at baseline, midpoint, and end point.
• The primary outcome was symptom severity as measured by the Panic and Agoraphobia Scale (PAS).

Outcomes

• Both groups experienced statistically significant improvements in symptom severity over time. The differences in PAS score were -5.97 (95% CI, -8.49 to -3.44, P < .001) for Agoraphobia Free and -6.35 (95% CI, -8.82 to -3.87, P < .001) for Stress Free.
• There were no significant between-group differences in symptom severity.

Continue to: Conclusions/limitations

• This study is the first RCT to show that patients with agoraphobia could benefit from mobile-based interventions.
• Limitations: There was no waitlist control group. Limited information was collected about participant characteristics; there were no data on comorbid disorders, other psychological or physiological treatments, or other demographic characteristics such as ethnicity or computer literacy.

3. Everitt N, Broadbent J, Richardson B, et al. Exploring the features of an app-based just-in-time intervention for depression. J Affect Disord. 2021;291:279-287. doi:10.1016/j.jad.2021.05.021

The apps MoodTracker, ImproveYourMood, and ImproveYourMood+ deliver content “just in time” (in response to acute negative symptoms) to help patients with depression. In an RCT, Everitt et al⁷ evaluated delivering acute care for depressive mood states via a smartphone app. They sought to delineate whether symptom improvement was due to microintervention content, mood augmentation, or just-in-time prompts to use content.

Study design

• Participants (N = 235) from the general population who said they wanted to improve their mood were randomly assigned to a waitlist control group (n = 55) or 1 of 3 intervention groups: MoodTracker (monitoring-only; n = 58), ImproveYourMood (monitoring and content; n = 62), or ImproveYourMood+ (monitoring, content, and prompts; n = 60).
• The microintervention content provided by these apps consisted of 4 audio files of brief (2- to 3-minute) mindfulness and relaxation exercises. Participants used the assigned app for 3 weeks.
• Depressive symptoms, anxiety symptoms, and negative automatic thoughts were assessed at baseline, immediately following the intervention, and 1 month after the intervention using the 9-item Patient Health Questionnaire (PHQ-9), 7-item GAD scale (GAD-7), and 8-item Automatic Thoughts Questionnaire, respectively.

Outcomes

• Compared to the waitlist control group, participants in the ImproveYourMood group showed greater declines in depressive symptoms and anxiety symptoms (at follow-up only), and negative automatic thoughts (at both postintervention and follow-up).
• Those in the ImproveYourMood+ group only showed significantly greater improvements for automatic negative thoughts (at postintervention).
• MoodTracker participants did not differ from waitlist controls for any variables at any timepoints.

Continue to: Conclusions/limitations

• This study suggests that using microinterventions in acute settings can effectively reduce depressive symptoms both as they occur, and 1 to 2 months later.
• Limitations: The study featured a naturalistic design, where participants self-selected whether they wanted to use the program. Participants did not complete eligibility assessments or receive compensation, and the study had high dropout rates, ranging from 20% for the waitlist control group to 67% for the ImproveYourMood+ group.

4. McLean C, Davis CA, Miller M, et al. The effects of an exposure-based mobile app on symptoms of posttraumatic stress disorder in veterans: pilot randomized controlled trial. JMIR Mhealth Uhealth. 2022;10(11):e38951. doi:10.2196/38951

Veterans with PTSD face barriers when receiving trauma-focused treatments such as exposure therapy or CBT. Smartphone apps may help veterans self-treat and self-manage their PTSD symptoms. McLean et al⁸ studied the efficacy of Renew, a smartphone app that uses exposure therapy and social support to treat PTSD.

Study design

• In this pilot RCT, 93 veterans with clinically significant PTSD symptoms were randomly assigned to use the Renew app with and without support from a research staff member (active use group) or to a waitlist (delayed use group) for 6 weeks.
• The PTSD Checklist for DSM-5 (PCL-5) was used to measure PTSD symptoms at preintervention, postintervention, and 6-week follow-up.
• Most participants (69%) were women, and the mean age was 49.

Outcomes

• Compared to the delayed use group, participants in the active use group experienced a larger decrease in PCL-5 score (-6.14 vs -1.84). However, this difference was not statistically significant (P = .29), and the effect size was small (d = -0.39).
• There was no difference in engagement with the app between participants who received support from a research staff member and those who did not receive such support.

Continue to: Conclusions/limitations

• Renew may show promise as a tool to reduce PTSD symptoms in veterans.
• Educating family and friends on how to best support a patient using a mobile mental health app may help improve the efficacy of Renew and increase app engagement.
• Limitations: Because the study was conducted in veterans, the results may not be generalizable to other populations. Because most data collection occurred during the first wave of the COVID-19 pandemic in the United States, COVID-19–related stress may have impacted PTSD symptoms, app engagement, or outcomes.

5. Graham AK, Greene CJ, Kwasny MJ, et al. Coached mobile app platform for the treatment of depression and anxiety among primary care patients: a randomized clinical trial. JAMA Psychiatry. 2020;77(9):906-914. doi:10.1001/jamapsychiatry.2020.1011

Many cases of depression and anxiety are initially treated in primary care settings. However, these settings may have limited resources and inadequate training, and mobile interventions might be helpful to augment patient care. Graham et al⁹ studied the mobile platform IntelliCare to determine its efficacy as a tool to be used in primary care settings to treat depression and anxiety.

Study design

• This RCT randomly assigned adult primary care patients (N = 146) who screened positive for depression on the PHQ-9 (score ≥10) or anxiety on the GAD-7 (score ≥8) to the coach-supported IntelliCare platform, which consisted of 5 clinically focused apps, or to a waitlist control group. Interventions were delivered over 8 weeks.
• Overall, 122 (83.6%) patients were diagnosed with depression and 131 (89.7%) were diagnosed with anxiety.
• The primary outcomes were changes in depression (as measured by change in PHQ-9 score) and anxiety (change in GAD-7 score) during the intervention period.

Outcomes

• Participants who used the IntelliCare platform had a greater reduction in depression and anxiety symptoms compared to waitlist controls, and changes were sustained over 2-month follow-up.
• The least square means (LSM) difference in depression scores at Week 4 was 2.91 (SE = 0.83; d = 0.43) and at Week 8 was 4.37 (SE = 0.83; d = 0.64). The LSM difference in anxiety scores at Week 4 was 2.51 (SE = 0.78; d = 0.41) and at Week 8 was 3.33 (SE = 0.76; d = 0.55).
• A median number of 93 and 98 sessions among participants with depression and anxiety were recorded, respectively, indicating high use of the IntelliCare platform.

Continue to: Conclusions/limitations

• The IntelliCare platform was shown to be effective in reducing depression and anxiety among primary care patients. Simple apps can be bundled together and used by patients in conjunction to treat their individual needs.
• Limitations: The study had a limited follow-up period and did not record participants’ use of other apps. Slightly more than one-half (56%) of participants were taking an antidepressant.

6. Wilhelm S, Weingarden H, Greenberg JL, et al. Efficacy of app-based cognitive behavioral therapy for body dysmorphic disorder with coach support: initial randomized controlled clinical trial. Psychother Psychosom. 2022;91(4):277-285. doi:10.1159/000524628

Body dysmorphic disorder (BDD) is a severe yet undertreated disorder. Apps can improve access to treatment for patients experiencing BDD. Wilhelm et al¹⁰ studied the usability and efficacy of a coach-supported app called Perspectives that was specifically designed for treating BDD. Perspectives provide CBT in 7 modules: psychoeducation, cognitive restructuring, exposure, response prevention, mindfulness, attention retraining, and relapse prevention.

Study design

• Adults (N = 80) with primary BDD were assigned to use the Perspectives app for 12 weeks or to a waitlist control group. Participants were predominately female (84%) and White (71%), with a mean age of 27.
• Coaches promoted engagement and answered questions via in-app messaging and phone calls.
• Blinded independent evaluators used the Yale-Brown Obsessive Compulsive Scale Modified for BDD (BDD-YBOCS) to measure BDD severity at baseline, midtreatment (Week 6), and end of treatment (Week 12).
• Secondary outcomes included BDD-related insight, depression, quality of life, and functioning. Various scales were used to measure these outcomes.

Outcomes

• In intent-to-treat analyses, patients who received CBT via the Perspectives app had significantly lower BDD severity at the end of treatment compared to the waitlist control group, with a mean (SD) BDD-YBOCS score of 16.8 (7.5) vs 26.7 (6.2), with P < .001 and d = 1.44.
• Slightly more than one-half (52%) of those who used Perspectives achieved full or partial remission, compared to 8% in the waitlist control group.

Continue to: Conclusions/limitations

• CBT delivered via the Perspectives app and a coach proved to be effective treatment for adults with BDD.
• Adoption of the application was relatively high; 86% of Perspectives users were very or mostly satisfied.
• Limitations: Because the participants in this study were predominantly female and White, the findings might not be generalizable to other populations.

7. Kuhn E, Miller KE, Puran D, et al. A pilot randomized controlled trial of the Insomnia Coach mobile app to assess its feasibility, acceptability, and potential efficacy. Behav Ther. 2022;53(3):440-457. doi:10.1016/j.beth.2021.11.003

Insomnia remains a substantial problem among military veterans. First-line treatments for the disorder are sleep hygiene modification and CBT. Access to CBT is limited, especially for veterans. Kuhn et al¹¹ studied the effectiveness of using Insomnia Coach, a CBT for insomnia–based app, to improve insomnia symptoms.

Study design

• Fifty US veterans who were mostly male (58%) with a mean age of 44.5 and moderate insomnia symptoms were randomized to use Insomnia Coach (n = 25) or to a waitlist control group (n = 25) for 6 weeks.
• All participants completed self-report measures and sleep diaries at baseline, posttreatment, and follow-up (12 weeks). Those who used the app (n = 15) completed a qualitative interview at posttreatment.

Outcomes

• At posttreatment, 28% of participants who used Insomnia Coach achieved clinically significant improvement, vs 4% of waitlist control participants. There was also a significant treatment effect on daytime sleep-related impairment (P = .044, d = -0.6).
• Additional treatment effects emerged at follow-up for insomnia severity, sleep onset latency, global sleep quality, and depression symptoms.
• Based on self-reports and qualitative interview responses, participants’ perceptions of Insomnia Coach were favorable. Three-fourths of participants used the app through 6 weeks and engaged with active elements.

Continue to: Conclusions/limitations

• Insomnia Coach may provide an accessible and convenient public health intervention for patients who aren’t receiving adequate care or CBT.
• Limitations: Because this study evaluated only veterans, the findings might not be generalizable to other populations.

8. Dahne J, Lejuez CW, Diaz VA, et al. Pilot randomized trial of a self-help behavioral activation mobile app for utilization in primary care. Behav Ther. 2019;50(4):817-827. doi:10.1016/j.beth.2018.12.003

Previous mobile technologies have shown the ability to treat depression in primary care settings. Moodivate is a self-help mobile app based on the Brief Behavioral Activation Treatment for Depression, which is an evidence-based treatment. This app is designed to help the user reengage in positive, nondepressed activities by identifying, scheduling, and completing activities. Dahne et al¹² investigated the feasibility and efficacy of Moodivate for depressive symptoms in primary care patients.

Study design

• Participants (N = 52) were recruited from primary care practices and randomized 2:2:1 to receive Moodivate, a CBT-based mobile app called MoodKit, or treatment as usual (no app). All participants had an initial PHQ-8 score >10.
• Participants completed assessments of depressive symptoms (PHQ-8) weekly for 8 weeks.
• App analytics data were captured to examine if the use of Moodivate was feasible. (Analytics were not available for MoodKit).

Outcomes

• Participants who used Moodivate had a mean (SD) of 46.76 (30.10) sessions throughout the trial, spent 3.50 (2.76) minutes using the app per session, and spent 120.76 (101.02) minutes using the app in total.
• Nearly 70% of Moodivate participants continued to use the app 1 month after trial enrollment and 50% at the end of the 8-week follow-up period.
• Compared to the treatment as usual group, participants who used Moodivate and those who used MoodKit experienced significant decreases in depressive symptoms over time.

Conclusions/limitations

• The results show that for primary care patients with depression, the use of Moodivate is feasible and may reduce depressive symptoms.
• Limitations: For the first 3 months of enrollment, patients who met diagnostic criteria for a current major depressive episode were excluded. This study did not assess duration of medication use (ie, whether a study participant was stabilized on medication or recently started taking a new medication) and therefore could not ascertain whether treatment gains were a result of the use of the app or of possible new medication use.

COVID-19’s increased demand on the mental health care delivery system led to expanded utilization of technology-based solutions, including digital tools to deliver care.¹ Technology-based solutions include both synchronous telehealth (eg, real-time interactive audio/video visits) and asynchronous tools such as smartphone applications (apps). Both real-time telehealth and apps continue to gain popularity. More than 10,000 mental health–related apps are available, and that number continues to rise.² Numerous web- or mobile-based apps are available to aid in the treatment of various psychiatric conditions, including generalized anxiety disorder (GAD), major depressive disorder, insomnia, and posttraumatic stress disorder (PTSD).

Clinicians may find it challenging to choose the best psychiatry-related apps to recommend to patients. This dilemma calls for an approach to help clinicians select apps that are safe and effective.² The American Psychiatric Association provides information to help mental health professionals navigate these issues and identify which aspects to consider when selecting an app for clinical use.³ The M-Health Index and Navigation Database also provides a set of objective evaluative criteria and offers guidance on choosing apps.⁴

In this article, we review 8 randomized controlled trials (RCTs) of mental health–related apps. We took several steps to ensure the RCTs we included were impactful and meaningful. First, we conducted a general search using mainstream search engines to assess which psychiatric apps were most popular for use in clinical practice. Using this list, we conducted a scholarly search engine query of RCTs using the name of the apps as a search parameter along with the following keywords: “mobile,” “web,” “applications,” and “psychiatry.” This search yielded approximately 50 results, which were narrowed down based on content and interest to a list of 8 articles (Table^5-12). These articles were then graded using the limitations of each study as the primary substrate for evaluation.

1. Linardon J, Shatte A, Rosato J, et al. Efficacy of a transdiagnostic cognitive-behavioral intervention for eating disorder psychopathology delivered through a smartphone app: a randomized controlled trial. Psychol Med. 2022;52(9):1679-1690. doi:10.1017/S0033291720003426

Many patients with eating disorders are unable to receive effective treatment due to problems with accessing health care. Smartphone apps may help bridge the treatment gap for patients in this position. Linardon et al⁵ developed an app that uses the principles of cognitive-behavioral therapy (CBT) for treating eating disorders and conducted this study to evaluate its effectiveness.

Study design

• This RCT assigned individuals who reported episodes of binge eating to a group that used a mobile app (n = 197) or to a waiting list (n = 195). At baseline, 42% of participants exhibited diagnostic-level symptoms of bulimia nervosa and 31% had symptoms of binge-eating disorder.
• Assessments took place at baseline, Week 4, and Week 8.
• The primary outcome was global levels of eating disorder psychopathology.
• Secondary outcomes were other eating disorder symptoms, impairment, and distress.

Outcomes

• Compared to the control group, participants who used the mobile app reported greater reductions in global eating disorder psychopathology (d = -0.80).
• Significant effects were also observed for secondary outcomes except compensatory behavior frequency.
• Overall, participants reported they were satisfied with the app.

Continue to: Conclusions/limitations

• Findings show this app could potentially be a cost-effective and easily accessible option for patients who cannot receive standard treatment for eating disorders.
• Limitations: The overall posttest attrition rate was 35%.

2. Christoforou M, Sáez Fonseca JA, Tsakanikos E. Two novel cognitive behavioral therapy–based mobile apps for agoraphobia: randomized controlled trial. J Med Internet Res. 2017;19(11):e398. doi:10.2196/jmir.7747

CBT is generally the most accepted first-line treatment for agoraphobia. However, numerous barriers to obtaining CBT can prevent successful treatment. Limited research has evaluated the efficacy of apps for treating agoraphobia. Christoforou et al⁶ conducted an RCT to determine the effectiveness of a self-guided smartphone app for improving agoraphobic symptoms, compared to a mobile app used to treat anxiety.

Study design

• Participants (N = 170) who self-identified as having agoraphobia were randomly assigned to use a smartphone app designed to target agoraphobia (Agoraphobia Free) or a smartphone app designed to help with symptoms of anxiety (Stress Free) for 12 weeks. Both apps were based on established cognitive behavioral principles.
• Assessment occurred at baseline, midpoint, and end point.
• The primary outcome was symptom severity as measured by the Panic and Agoraphobia Scale (PAS).

Outcomes

• Both groups experienced statistically significant improvements in symptom severity over time. The differences in PAS score were -5.97 (95% CI, -8.49 to -3.44, P < .001) for Agoraphobia Free and -6.35 (95% CI, -8.82 to -3.87, P < .001) for Stress Free.
• There were no significant between-group differences in symptom severity.

Continue to: Conclusions/limitations

• This study is the first RCT to show that patients with agoraphobia could benefit from mobile-based interventions.
• Limitations: There was no waitlist control group. Limited information was collected about participant characteristics; there were no data on comorbid disorders, other psychological or physiological treatments, or other demographic characteristics such as ethnicity or computer literacy.

3. Everitt N, Broadbent J, Richardson B, et al. Exploring the features of an app-based just-in-time intervention for depression. J Affect Disord. 2021;291:279-287. doi:10.1016/j.jad.2021.05.021

The apps MoodTracker, ImproveYourMood, and ImproveYourMood+ deliver content “just in time” (in response to acute negative symptoms) to help patients with depression. In an RCT, Everitt et al⁷ evaluated delivering acute care for depressive mood states via a smartphone app. They sought to delineate whether symptom improvement was due to microintervention content, mood augmentation, or just-in-time prompts to use content.

Study design

• Participants (N = 235) from the general population who said they wanted to improve their mood were randomly assigned to a waitlist control group (n = 55) or 1 of 3 intervention groups: MoodTracker (monitoring-only; n = 58), ImproveYourMood (monitoring and content; n = 62), or ImproveYourMood+ (monitoring, content, and prompts; n = 60).
• The microintervention content provided by these apps consisted of 4 audio files of brief (2- to 3-minute) mindfulness and relaxation exercises. Participants used the assigned app for 3 weeks.
• Depressive symptoms, anxiety symptoms, and negative automatic thoughts were assessed at baseline, immediately following the intervention, and 1 month after the intervention using the 9-item Patient Health Questionnaire (PHQ-9), 7-item GAD scale (GAD-7), and 8-item Automatic Thoughts Questionnaire, respectively.

Outcomes

• Compared to the waitlist control group, participants in the ImproveYourMood group showed greater declines in depressive symptoms and anxiety symptoms (at follow-up only), and negative automatic thoughts (at both postintervention and follow-up).
• Those in the ImproveYourMood+ group only showed significantly greater improvements for automatic negative thoughts (at postintervention).
• MoodTracker participants did not differ from waitlist controls for any variables at any timepoints.

Continue to: Conclusions/limitations

• This study suggests that using microinterventions in acute settings can effectively reduce depressive symptoms both as they occur, and 1 to 2 months later.
• Limitations: The study featured a naturalistic design, where participants self-selected whether they wanted to use the program. Participants did not complete eligibility assessments or receive compensation, and the study had high dropout rates, ranging from 20% for the waitlist control group to 67% for the ImproveYourMood+ group.

4. McLean C, Davis CA, Miller M, et al. The effects of an exposure-based mobile app on symptoms of posttraumatic stress disorder in veterans: pilot randomized controlled trial. JMIR Mhealth Uhealth. 2022;10(11):e38951. doi:10.2196/38951

Veterans with PTSD face barriers when receiving trauma-focused treatments such as exposure therapy or CBT. Smartphone apps may help veterans self-treat and self-manage their PTSD symptoms. McLean et al⁸ studied the efficacy of Renew, a smartphone app that uses exposure therapy and social support to treat PTSD.

Study design

• In this pilot RCT, 93 veterans with clinically significant PTSD symptoms were randomly assigned to use the Renew app with and without support from a research staff member (active use group) or to a waitlist (delayed use group) for 6 weeks.
• The PTSD Checklist for DSM-5 (PCL-5) was used to measure PTSD symptoms at preintervention, postintervention, and 6-week follow-up.
• Most participants (69%) were women, and the mean age was 49.

Outcomes

• Compared to the delayed use group, participants in the active use group experienced a larger decrease in PCL-5 score (-6.14 vs -1.84). However, this difference was not statistically significant (P = .29), and the effect size was small (d = -0.39).
• There was no difference in engagement with the app between participants who received support from a research staff member and those who did not receive such support.

Continue to: Conclusions/limitations

• Renew may show promise as a tool to reduce PTSD symptoms in veterans.
• Educating family and friends on how to best support a patient using a mobile mental health app may help improve the efficacy of Renew and increase app engagement.
• Limitations: Because the study was conducted in veterans, the results may not be generalizable to other populations. Because most data collection occurred during the first wave of the COVID-19 pandemic in the United States, COVID-19–related stress may have impacted PTSD symptoms, app engagement, or outcomes.

5. Graham AK, Greene CJ, Kwasny MJ, et al. Coached mobile app platform for the treatment of depression and anxiety among primary care patients: a randomized clinical trial. JAMA Psychiatry. 2020;77(9):906-914. doi:10.1001/jamapsychiatry.2020.1011

Many cases of depression and anxiety are initially treated in primary care settings. However, these settings may have limited resources and inadequate training, and mobile interventions might be helpful to augment patient care. Graham et al⁹ studied the mobile platform IntelliCare to determine its efficacy as a tool to be used in primary care settings to treat depression and anxiety.

Study design

• This RCT randomly assigned adult primary care patients (N = 146) who screened positive for depression on the PHQ-9 (score ≥10) or anxiety on the GAD-7 (score ≥8) to the coach-supported IntelliCare platform, which consisted of 5 clinically focused apps, or to a waitlist control group. Interventions were delivered over 8 weeks.
• Overall, 122 (83.6%) patients were diagnosed with depression and 131 (89.7%) were diagnosed with anxiety.
• The primary outcomes were changes in depression (as measured by change in PHQ-9 score) and anxiety (change in GAD-7 score) during the intervention period.

Outcomes

• Participants who used the IntelliCare platform had a greater reduction in depression and anxiety symptoms compared to waitlist controls, and changes were sustained over 2-month follow-up.
• The least square means (LSM) difference in depression scores at Week 4 was 2.91 (SE = 0.83; d = 0.43) and at Week 8 was 4.37 (SE = 0.83; d = 0.64). The LSM difference in anxiety scores at Week 4 was 2.51 (SE = 0.78; d = 0.41) and at Week 8 was 3.33 (SE = 0.76; d = 0.55).
• A median number of 93 and 98 sessions among participants with depression and anxiety were recorded, respectively, indicating high use of the IntelliCare platform.

Continue to: Conclusions/limitations

• The IntelliCare platform was shown to be effective in reducing depression and anxiety among primary care patients. Simple apps can be bundled together and used by patients in conjunction to treat their individual needs.
• Limitations: The study had a limited follow-up period and did not record participants’ use of other apps. Slightly more than one-half (56%) of participants were taking an antidepressant.

6. Wilhelm S, Weingarden H, Greenberg JL, et al. Efficacy of app-based cognitive behavioral therapy for body dysmorphic disorder with coach support: initial randomized controlled clinical trial. Psychother Psychosom. 2022;91(4):277-285. doi:10.1159/000524628

Body dysmorphic disorder (BDD) is a severe yet undertreated disorder. Apps can improve access to treatment for patients experiencing BDD. Wilhelm et al¹⁰ studied the usability and efficacy of a coach-supported app called Perspectives that was specifically designed for treating BDD. Perspectives provide CBT in 7 modules: psychoeducation, cognitive restructuring, exposure, response prevention, mindfulness, attention retraining, and relapse prevention.

Study design

• Adults (N = 80) with primary BDD were assigned to use the Perspectives app for 12 weeks or to a waitlist control group. Participants were predominately female (84%) and White (71%), with a mean age of 27.
• Coaches promoted engagement and answered questions via in-app messaging and phone calls.
• Blinded independent evaluators used the Yale-Brown Obsessive Compulsive Scale Modified for BDD (BDD-YBOCS) to measure BDD severity at baseline, midtreatment (Week 6), and end of treatment (Week 12).
• Secondary outcomes included BDD-related insight, depression, quality of life, and functioning. Various scales were used to measure these outcomes.

Outcomes

• In intent-to-treat analyses, patients who received CBT via the Perspectives app had significantly lower BDD severity at the end of treatment compared to the waitlist control group, with a mean (SD) BDD-YBOCS score of 16.8 (7.5) vs 26.7 (6.2), with P < .001 and d = 1.44.
• Slightly more than one-half (52%) of those who used Perspectives achieved full or partial remission, compared to 8% in the waitlist control group.

Continue to: Conclusions/limitations

• CBT delivered via the Perspectives app and a coach proved to be effective treatment for adults with BDD.
• Adoption of the application was relatively high; 86% of Perspectives users were very or mostly satisfied.
• Limitations: Because the participants in this study were predominantly female and White, the findings might not be generalizable to other populations.

7. Kuhn E, Miller KE, Puran D, et al. A pilot randomized controlled trial of the Insomnia Coach mobile app to assess its feasibility, acceptability, and potential efficacy. Behav Ther. 2022;53(3):440-457. doi:10.1016/j.beth.2021.11.003

Insomnia remains a substantial problem among military veterans. First-line treatments for the disorder are sleep hygiene modification and CBT. Access to CBT is limited, especially for veterans. Kuhn et al¹¹ studied the effectiveness of using Insomnia Coach, a CBT for insomnia–based app, to improve insomnia symptoms.

Study design

• Fifty US veterans who were mostly male (58%) with a mean age of 44.5 and moderate insomnia symptoms were randomized to use Insomnia Coach (n = 25) or to a waitlist control group (n = 25) for 6 weeks.
• All participants completed self-report measures and sleep diaries at baseline, posttreatment, and follow-up (12 weeks). Those who used the app (n = 15) completed a qualitative interview at posttreatment.

Outcomes

• At posttreatment, 28% of participants who used Insomnia Coach achieved clinically significant improvement, vs 4% of waitlist control participants. There was also a significant treatment effect on daytime sleep-related impairment (P = .044, d = -0.6).
• Additional treatment effects emerged at follow-up for insomnia severity, sleep onset latency, global sleep quality, and depression symptoms.
• Based on self-reports and qualitative interview responses, participants’ perceptions of Insomnia Coach were favorable. Three-fourths of participants used the app through 6 weeks and engaged with active elements.

Continue to: Conclusions/limitations

• Insomnia Coach may provide an accessible and convenient public health intervention for patients who aren’t receiving adequate care or CBT.
• Limitations: Because this study evaluated only veterans, the findings might not be generalizable to other populations.

8. Dahne J, Lejuez CW, Diaz VA, et al. Pilot randomized trial of a self-help behavioral activation mobile app for utilization in primary care. Behav Ther. 2019;50(4):817-827. doi:10.1016/j.beth.2018.12.003

Previous mobile technologies have shown the ability to treat depression in primary care settings. Moodivate is a self-help mobile app based on the Brief Behavioral Activation Treatment for Depression, which is an evidence-based treatment. This app is designed to help the user reengage in positive, nondepressed activities by identifying, scheduling, and completing activities. Dahne et al¹² investigated the feasibility and efficacy of Moodivate for depressive symptoms in primary care patients.

Study design

• Participants (N = 52) were recruited from primary care practices and randomized 2:2:1 to receive Moodivate, a CBT-based mobile app called MoodKit, or treatment as usual (no app). All participants had an initial PHQ-8 score >10.
• Participants completed assessments of depressive symptoms (PHQ-8) weekly for 8 weeks.
• App analytics data were captured to examine if the use of Moodivate was feasible. (Analytics were not available for MoodKit).

Outcomes

• Participants who used Moodivate had a mean (SD) of 46.76 (30.10) sessions throughout the trial, spent 3.50 (2.76) minutes using the app per session, and spent 120.76 (101.02) minutes using the app in total.
• Nearly 70% of Moodivate participants continued to use the app 1 month after trial enrollment and 50% at the end of the 8-week follow-up period.
• Compared to the treatment as usual group, participants who used Moodivate and those who used MoodKit experienced significant decreases in depressive symptoms over time.

Conclusions/limitations

• The results show that for primary care patients with depression, the use of Moodivate is feasible and may reduce depressive symptoms.
• Limitations: For the first 3 months of enrollment, patients who met diagnostic criteria for a current major depressive episode were excluded. This study did not assess duration of medication use (ie, whether a study participant was stabilized on medication or recently started taking a new medication) and therefore could not ascertain whether treatment gains were a result of the use of the app or of possible new medication use.

COVID-19’s increased demand on the mental health care delivery system led to expanded utilization of technology-based solutions, including digital tools to deliver care.¹ Technology-based solutions include both synchronous telehealth (eg, real-time interactive audio/video visits) and asynchronous tools such as smartphone applications (apps). Both real-time telehealth and apps continue to gain popularity. More than 10,000 mental health–related apps are available, and that number continues to rise.² Numerous web- or mobile-based apps are available to aid in the treatment of various psychiatric conditions, including generalized anxiety disorder (GAD), major depressive disorder, insomnia, and posttraumatic stress disorder (PTSD).

Clinicians may find it challenging to choose the best psychiatry-related apps to recommend to patients. This dilemma calls for an approach to help clinicians select apps that are safe and effective.² The American Psychiatric Association provides information to help mental health professionals navigate these issues and identify which aspects to consider when selecting an app for clinical use.³ The M-Health Index and Navigation Database also provides a set of objective evaluative criteria and offers guidance on choosing apps.⁴

In this article, we review 8 randomized controlled trials (RCTs) of mental health–related apps. We took several steps to ensure the RCTs we included were impactful and meaningful. First, we conducted a general search using mainstream search engines to assess which psychiatric apps were most popular for use in clinical practice. Using this list, we conducted a scholarly search engine query of RCTs using the name of the apps as a search parameter along with the following keywords: “mobile,” “web,” “applications,” and “psychiatry.” This search yielded approximately 50 results, which were narrowed down based on content and interest to a list of 8 articles (Table^5-12). These articles were then graded using the limitations of each study as the primary substrate for evaluation.

1. Linardon J, Shatte A, Rosato J, et al. Efficacy of a transdiagnostic cognitive-behavioral intervention for eating disorder psychopathology delivered through a smartphone app: a randomized controlled trial. Psychol Med. 2022;52(9):1679-1690. doi:10.1017/S0033291720003426

Many patients with eating disorders are unable to receive effective treatment due to problems with accessing health care. Smartphone apps may help bridge the treatment gap for patients in this position. Linardon et al⁵ developed an app that uses the principles of cognitive-behavioral therapy (CBT) for treating eating disorders and conducted this study to evaluate its effectiveness.

Study design

• This RCT assigned individuals who reported episodes of binge eating to a group that used a mobile app (n = 197) or to a waiting list (n = 195). At baseline, 42% of participants exhibited diagnostic-level symptoms of bulimia nervosa and 31% had symptoms of binge-eating disorder.
• Assessments took place at baseline, Week 4, and Week 8.
• The primary outcome was global levels of eating disorder psychopathology.
• Secondary outcomes were other eating disorder symptoms, impairment, and distress.

Outcomes

• Compared to the control group, participants who used the mobile app reported greater reductions in global eating disorder psychopathology (d = -0.80).
• Significant effects were also observed for secondary outcomes except compensatory behavior frequency.
• Overall, participants reported they were satisfied with the app.

Continue to: Conclusions/limitations

• Findings show this app could potentially be a cost-effective and easily accessible option for patients who cannot receive standard treatment for eating disorders.
• Limitations: The overall posttest attrition rate was 35%.

2. Christoforou M, Sáez Fonseca JA, Tsakanikos E. Two novel cognitive behavioral therapy–based mobile apps for agoraphobia: randomized controlled trial. J Med Internet Res. 2017;19(11):e398. doi:10.2196/jmir.7747

CBT is generally the most accepted first-line treatment for agoraphobia. However, numerous barriers to obtaining CBT can prevent successful treatment. Limited research has evaluated the efficacy of apps for treating agoraphobia. Christoforou et al⁶ conducted an RCT to determine the effectiveness of a self-guided smartphone app for improving agoraphobic symptoms, compared to a mobile app used to treat anxiety.

Study design

• Participants (N = 170) who self-identified as having agoraphobia were randomly assigned to use a smartphone app designed to target agoraphobia (Agoraphobia Free) or a smartphone app designed to help with symptoms of anxiety (Stress Free) for 12 weeks. Both apps were based on established cognitive behavioral principles.
• Assessment occurred at baseline, midpoint, and end point.
• The primary outcome was symptom severity as measured by the Panic and Agoraphobia Scale (PAS).

Outcomes

• Both groups experienced statistically significant improvements in symptom severity over time. The differences in PAS score were -5.97 (95% CI, -8.49 to -3.44, P < .001) for Agoraphobia Free and -6.35 (95% CI, -8.82 to -3.87, P < .001) for Stress Free.
• There were no significant between-group differences in symptom severity.

Continue to: Conclusions/limitations

• This study is the first RCT to show that patients with agoraphobia could benefit from mobile-based interventions.
• Limitations: There was no waitlist control group. Limited information was collected about participant characteristics; there were no data on comorbid disorders, other psychological or physiological treatments, or other demographic characteristics such as ethnicity or computer literacy.

3. Everitt N, Broadbent J, Richardson B, et al. Exploring the features of an app-based just-in-time intervention for depression. J Affect Disord. 2021;291:279-287. doi:10.1016/j.jad.2021.05.021

The apps MoodTracker, ImproveYourMood, and ImproveYourMood+ deliver content “just in time” (in response to acute negative symptoms) to help patients with depression. In an RCT, Everitt et al⁷ evaluated delivering acute care for depressive mood states via a smartphone app. They sought to delineate whether symptom improvement was due to microintervention content, mood augmentation, or just-in-time prompts to use content.

Study design

• Participants (N = 235) from the general population who said they wanted to improve their mood were randomly assigned to a waitlist control group (n = 55) or 1 of 3 intervention groups: MoodTracker (monitoring-only; n = 58), ImproveYourMood (monitoring and content; n = 62), or ImproveYourMood+ (monitoring, content, and prompts; n = 60).
• The microintervention content provided by these apps consisted of 4 audio files of brief (2- to 3-minute) mindfulness and relaxation exercises. Participants used the assigned app for 3 weeks.
• Depressive symptoms, anxiety symptoms, and negative automatic thoughts were assessed at baseline, immediately following the intervention, and 1 month after the intervention using the 9-item Patient Health Questionnaire (PHQ-9), 7-item GAD scale (GAD-7), and 8-item Automatic Thoughts Questionnaire, respectively.

Outcomes

• Compared to the waitlist control group, participants in the ImproveYourMood group showed greater declines in depressive symptoms and anxiety symptoms (at follow-up only), and negative automatic thoughts (at both postintervention and follow-up).
• Those in the ImproveYourMood+ group only showed significantly greater improvements for automatic negative thoughts (at postintervention).
• MoodTracker participants did not differ from waitlist controls for any variables at any timepoints.

Continue to: Conclusions/limitations

• This study suggests that using microinterventions in acute settings can effectively reduce depressive symptoms both as they occur, and 1 to 2 months later.
• Limitations: The study featured a naturalistic design, where participants self-selected whether they wanted to use the program. Participants did not complete eligibility assessments or receive compensation, and the study had high dropout rates, ranging from 20% for the waitlist control group to 67% for the ImproveYourMood+ group.

4. McLean C, Davis CA, Miller M, et al. The effects of an exposure-based mobile app on symptoms of posttraumatic stress disorder in veterans: pilot randomized controlled trial. JMIR Mhealth Uhealth. 2022;10(11):e38951. doi:10.2196/38951

Veterans with PTSD face barriers when receiving trauma-focused treatments such as exposure therapy or CBT. Smartphone apps may help veterans self-treat and self-manage their PTSD symptoms. McLean et al⁸ studied the efficacy of Renew, a smartphone app that uses exposure therapy and social support to treat PTSD.

Study design

• In this pilot RCT, 93 veterans with clinically significant PTSD symptoms were randomly assigned to use the Renew app with and without support from a research staff member (active use group) or to a waitlist (delayed use group) for 6 weeks.
• The PTSD Checklist for DSM-5 (PCL-5) was used to measure PTSD symptoms at preintervention, postintervention, and 6-week follow-up.
• Most participants (69%) were women, and the mean age was 49.

Outcomes

• Compared to the delayed use group, participants in the active use group experienced a larger decrease in PCL-5 score (-6.14 vs -1.84). However, this difference was not statistically significant (P = .29), and the effect size was small (d = -0.39).
• There was no difference in engagement with the app between participants who received support from a research staff member and those who did not receive such support.

Continue to: Conclusions/limitations

• Renew may show promise as a tool to reduce PTSD symptoms in veterans.
• Educating family and friends on how to best support a patient using a mobile mental health app may help improve the efficacy of Renew and increase app engagement.
• Limitations: Because the study was conducted in veterans, the results may not be generalizable to other populations. Because most data collection occurred during the first wave of the COVID-19 pandemic in the United States, COVID-19–related stress may have impacted PTSD symptoms, app engagement, or outcomes.

5. Graham AK, Greene CJ, Kwasny MJ, et al. Coached mobile app platform for the treatment of depression and anxiety among primary care patients: a randomized clinical trial. JAMA Psychiatry. 2020;77(9):906-914. doi:10.1001/jamapsychiatry.2020.1011

Many cases of depression and anxiety are initially treated in primary care settings. However, these settings may have limited resources and inadequate training, and mobile interventions might be helpful to augment patient care. Graham et al⁹ studied the mobile platform IntelliCare to determine its efficacy as a tool to be used in primary care settings to treat depression and anxiety.

Study design

• This RCT randomly assigned adult primary care patients (N = 146) who screened positive for depression on the PHQ-9 (score ≥10) or anxiety on the GAD-7 (score ≥8) to the coach-supported IntelliCare platform, which consisted of 5 clinically focused apps, or to a waitlist control group. Interventions were delivered over 8 weeks.
• Overall, 122 (83.6%) patients were diagnosed with depression and 131 (89.7%) were diagnosed with anxiety.
• The primary outcomes were changes in depression (as measured by change in PHQ-9 score) and anxiety (change in GAD-7 score) during the intervention period.

Outcomes

• Participants who used the IntelliCare platform had a greater reduction in depression and anxiety symptoms compared to waitlist controls, and changes were sustained over 2-month follow-up.
• The least square means (LSM) difference in depression scores at Week 4 was 2.91 (SE = 0.83; d = 0.43) and at Week 8 was 4.37 (SE = 0.83; d = 0.64). The LSM difference in anxiety scores at Week 4 was 2.51 (SE = 0.78; d = 0.41) and at Week 8 was 3.33 (SE = 0.76; d = 0.55).
• A median number of 93 and 98 sessions among participants with depression and anxiety were recorded, respectively, indicating high use of the IntelliCare platform.

Continue to: Conclusions/limitations

• The IntelliCare platform was shown to be effective in reducing depression and anxiety among primary care patients. Simple apps can be bundled together and used by patients in conjunction to treat their individual needs.
• Limitations: The study had a limited follow-up period and did not record participants’ use of other apps. Slightly more than one-half (56%) of participants were taking an antidepressant.

6. Wilhelm S, Weingarden H, Greenberg JL, et al. Efficacy of app-based cognitive behavioral therapy for body dysmorphic disorder with coach support: initial randomized controlled clinical trial. Psychother Psychosom. 2022;91(4):277-285. doi:10.1159/000524628

Body dysmorphic disorder (BDD) is a severe yet undertreated disorder. Apps can improve access to treatment for patients experiencing BDD. Wilhelm et al¹⁰ studied the usability and efficacy of a coach-supported app called Perspectives that was specifically designed for treating BDD. Perspectives provide CBT in 7 modules: psychoeducation, cognitive restructuring, exposure, response prevention, mindfulness, attention retraining, and relapse prevention.

Study design

• Adults (N = 80) with primary BDD were assigned to use the Perspectives app for 12 weeks or to a waitlist control group. Participants were predominately female (84%) and White (71%), with a mean age of 27.
• Coaches promoted engagement and answered questions via in-app messaging and phone calls.
• Blinded independent evaluators used the Yale-Brown Obsessive Compulsive Scale Modified for BDD (BDD-YBOCS) to measure BDD severity at baseline, midtreatment (Week 6), and end of treatment (Week 12).
• Secondary outcomes included BDD-related insight, depression, quality of life, and functioning. Various scales were used to measure these outcomes.

Outcomes

• In intent-to-treat analyses, patients who received CBT via the Perspectives app had significantly lower BDD severity at the end of treatment compared to the waitlist control group, with a mean (SD) BDD-YBOCS score of 16.8 (7.5) vs 26.7 (6.2), with P < .001 and d = 1.44.
• Slightly more than one-half (52%) of those who used Perspectives achieved full or partial remission, compared to 8% in the waitlist control group.

Continue to: Conclusions/limitations

• CBT delivered via the Perspectives app and a coach proved to be effective treatment for adults with BDD.
• Adoption of the application was relatively high; 86% of Perspectives users were very or mostly satisfied.
• Limitations: Because the participants in this study were predominantly female and White, the findings might not be generalizable to other populations.

7. Kuhn E, Miller KE, Puran D, et al. A pilot randomized controlled trial of the Insomnia Coach mobile app to assess its feasibility, acceptability, and potential efficacy. Behav Ther. 2022;53(3):440-457. doi:10.1016/j.beth.2021.11.003

Insomnia remains a substantial problem among military veterans. First-line treatments for the disorder are sleep hygiene modification and CBT. Access to CBT is limited, especially for veterans. Kuhn et al¹¹ studied the effectiveness of using Insomnia Coach, a CBT for insomnia–based app, to improve insomnia symptoms.

Study design

• Fifty US veterans who were mostly male (58%) with a mean age of 44.5 and moderate insomnia symptoms were randomized to use Insomnia Coach (n = 25) or to a waitlist control group (n = 25) for 6 weeks.
• All participants completed self-report measures and sleep diaries at baseline, posttreatment, and follow-up (12 weeks). Those who used the app (n = 15) completed a qualitative interview at posttreatment.

Outcomes

• At posttreatment, 28% of participants who used Insomnia Coach achieved clinically significant improvement, vs 4% of waitlist control participants. There was also a significant treatment effect on daytime sleep-related impairment (P = .044, d = -0.6).
• Additional treatment effects emerged at follow-up for insomnia severity, sleep onset latency, global sleep quality, and depression symptoms.
• Based on self-reports and qualitative interview responses, participants’ perceptions of Insomnia Coach were favorable. Three-fourths of participants used the app through 6 weeks and engaged with active elements.

Continue to: Conclusions/limitations

• Insomnia Coach may provide an accessible and convenient public health intervention for patients who aren’t receiving adequate care or CBT.
• Limitations: Because this study evaluated only veterans, the findings might not be generalizable to other populations.

8. Dahne J, Lejuez CW, Diaz VA, et al. Pilot randomized trial of a self-help behavioral activation mobile app for utilization in primary care. Behav Ther. 2019;50(4):817-827. doi:10.1016/j.beth.2018.12.003

Previous mobile technologies have shown the ability to treat depression in primary care settings. Moodivate is a self-help mobile app based on the Brief Behavioral Activation Treatment for Depression, which is an evidence-based treatment. This app is designed to help the user reengage in positive, nondepressed activities by identifying, scheduling, and completing activities. Dahne et al¹² investigated the feasibility and efficacy of Moodivate for depressive symptoms in primary care patients.

Study design

• Participants (N = 52) were recruited from primary care practices and randomized 2:2:1 to receive Moodivate, a CBT-based mobile app called MoodKit, or treatment as usual (no app). All participants had an initial PHQ-8 score >10.
• Participants completed assessments of depressive symptoms (PHQ-8) weekly for 8 weeks.
• App analytics data were captured to examine if the use of Moodivate was feasible. (Analytics were not available for MoodKit).

Outcomes

• Participants who used Moodivate had a mean (SD) of 46.76 (30.10) sessions throughout the trial, spent 3.50 (2.76) minutes using the app per session, and spent 120.76 (101.02) minutes using the app in total.
• Nearly 70% of Moodivate participants continued to use the app 1 month after trial enrollment and 50% at the end of the 8-week follow-up period.
• Compared to the treatment as usual group, participants who used Moodivate and those who used MoodKit experienced significant decreases in depressive symptoms over time.

Conclusions/limitations

• The results show that for primary care patients with depression, the use of Moodivate is feasible and may reduce depressive symptoms.
• Limitations: For the first 3 months of enrollment, patients who met diagnostic criteria for a current major depressive episode were excluded. This study did not assess duration of medication use (ie, whether a study participant was stabilized on medication or recently started taking a new medication) and therefore could not ascertain whether treatment gains were a result of the use of the app or of possible new medication use.

Ms. A, age 20, presents to the clinic after experiencing difficulty sleeping, depressed mood, fatigue, and difficulty concentrating. Her psychiatric history includes bipolar II disorder (BD II), predominantly with depressive episodes. Ms. A’s current medications include a combination of lamotrigine 200 mg/d and bupropion extended-release 450 mg/d, and her symptoms were well maintained until 2 weeks ago. When her psychiatrist performs a medication reconciliation at her medication management appointment, Ms. A indicates she started taking an oral contraceptive, ethinyl estradiol and norgestimate, approximately 1 month ago for management of endometriosis symptoms. She is not currently taking any other medications or supplements.

Lamotrigine is indicated for epilepsy and as maintenance treatment for BD I. It is also used off-label to treat other mood disorders. After oral administration, lamotrigine is rapidly and fully absorbed with a high bioavailability (98%).The principal metabolic pathway is via glucuronic acid conjugation, leading to the major inactive metabolite 2-N-glucuronide. Minor metabolites include 5-N-glucuronide and a 2-N-glucuronide metabolite.¹

Combined oral contraceptives contain an estrogen component, typically ethinyl estradiol, and a progestin component, which varies based on the specific formulation. The metabolism of ethinyl estradiol occurs through cytochrome P450 (CYP)3A4, CYP2C9, sulfation, and glucuronidation. For progestin—the second component of combined oral contraceptives and the lone com­ponent of progestin-only oral contraceptives—metabolism occurs via CYP3A4 and conjugation reactions.² This article focuses on lamotrigine interactions specifically with oral contraceptives, but it is important to note that other formulations of combined hormonal contraceptives, such as the combined contraceptive patch (Ortho Evra) and vaginal ring (NuvaRing), would be expected to interact in the same way as oral formulations.³

Bidirectional interaction

While many antiseizure medications are known to interact with and potentially decrease the efficacy of oral contraceptives (Table 1^3-6), the interactions between lamotrigine and oral contraceptives is uniquely bidirectional. Combined oral contraceptives are thought to interact with lamotrigine primarily via the estrogen component, which causes increased metabolism of lamotrigine through induction of glucuronidation. This drug interaction decreases the plasma concentrations of lamotrigine in the body by up to 2-fold, resulting in an increased risk of seizures or inadequate mood stabilization.¹ This effect on metabolism is very rapid, resulting in decreases in lamotrigine concentrations within 1 week.^4,7 A recent study suggested that certain progestins may also contribute to decreased plasma levels of lamotrigine, but the mechanism for this is unknown (Table 2^3-7).⁸

Clinicians should consider increasing the lamotrigine dose (potentially as much as 2-fold) in a patient who initiates treatment with a combined hormonal contraceptive. Dose increases should not be >50 to 100 mg/d every week.¹ Collect lamotrigine blood levels before starting a hormonal contraceptive and during dose titration. While there is not a well-established therapeutic range for lamotrigine in BD, expert consensus recommends a range of 1 to 6 mcg/mL.⁸

The lamotrigine dose should be decreased if combined hormonal contraceptives are discontinued. Dose decreases should not exceed 25% of the total daily dose per week.¹ Desogestrel, a progestin-only medication, may increase exposure to lamotrigine, but this has not been observed in research with other progestins.^5,9 When starting a progestin-only pill, monitor patients for signs of lamotrigine toxicity (ataxia, diplopia, dizziness) and consider monitoring their blood levels.

An important consideration to note with combined oral contraceptives is the hormone-free interval, also known as the pill-free week. Due to the rapid effect of estrogens, the lamotrigine concentrations have been shown to rise, even double, during this hormone-free interval, so patients should be closely monitored for adverse effects.³ Some recommend use of an extended cycle regimen (with a limited hormone-free interval), or continuous cycle regimen (with no hormone-free interval) to avoid fluctuations in lamotrigine levels.^3,5 Additionally, data suggest that in patients taking lamotrigine and valproate, which inhibits glucuronidation, oral contraceptives do not cause reductions in lamotrigine concentrations.^2,5 In these instances, dose increases of lamotrigine are not needed.

Continue to: The metabolism of ethinyl estradiol...

The metabolism of ethinyl estradiol and progestin are susceptible to CYP3A4 induction and increased glucuronidation. Serum concentrations may be reduced by ≥50% when used concomitantly with CYP enzyme–inducing medications, which could possibly result in subtherapeutic levels and unplanned pregnancy.³ CYP3A4 induction occurs for up to 4 weeks after discontinuation of an enzyme-inducing agent, pointing to the need for alternative or backup contraception during this time.³ Lamotrigine is not a CYP enzyme–inducing medication; it is unlikely to affect the efficacy of oral contraceptives in the same manner as other antiseizure medications. However, a study of lamotrigine and the combined hormonal contraceptive ethinyl estradiol and levonorgestrel demonstrated reduced exposure to levonorgestrel, resulting in breakthrough bleeding.⁵

In a study on the coadministration of lamotrigine and combined oral contraceptives, Sidhu et al⁴ observed a small mean reduction (20%) in progestin concentrations when lamotrigine was used at a dose of 300 mg/d. Although there is no research suggesting decreased effectiveness in preventing pregnancy when lamotrigine is used with combined oral contraceptives, progestin-only oral contraceptives, or progestin implants, additional or alternative contraceptive methods may be considered based on this pharmacokinetic data, particularly in patients who require lamotrigine doses ≥300 mg/d.⁵

CASE CONTINUED

Given when Ms. A started the oral contraceptive, the treatment team determines it is likely that an interaction with lamotrigine is causing her resurgence of depressive symptoms. Her care team decides to titrate the lamotrigine gradually to 300 mg/d, then 400 mg/d if needed, while carefully monitoring for signs of a serious rash. This dosage increase may help Ms. A achieve symptom remission. Monitoring plasma levels may be considered, although it is unknown what plasma level was effective for Ms. A before she started the oral contraceptive. Ms. A would need to be counseled regarding the effect of higher doses of lamotrigine on the effectiveness of the oral contraceptive.

Although it does not appear Ms. A is using the oral contraceptive specifically to prevent pregnancy, the team informs her about the possibility of unintended pregnancy with this medication combination. If Ms. A was also using the medication for this indication, alternative contraceptive options would include medroxyprogesterone acetate, levonorgestrel implants, or an intrauterine device (levonorgestrel or copper, though copper would not be effective for endometriosis symptom management). Ms. A should consult with her gynecologist regarding the most appropriate option for her endometriosis. If the decision is made to discontinue her oral contraceptive in the future, the lamotrigine dose should be decreased to her previously effective dose of 200 mg/d.

Related Resources

• Makino KK, Hatters Friedman S, Amin J. Emergency contraception for psychiatric patients. Current Psychiatry. 2022;21(11):34-39,44-45. doi:10.12788/cp.0300
• MGH Center for Women’s Mental Health. You asked: is there an interaction between lamotrigine and oral contraceptives? September 29, 2015. https://womensmentalhealth.org/posts/you-asked-is-there-an-interaction-between-lamotrigine-andoral-contraceptives/

Drug Brand Names

Bupropion extended-release • Wellbutrin XL
Carbamazepine • Equetro, Tegretol
Desogestrel • Cerazette
Divalproex sodium • Depakote
Ethinyl estradiol and etonogestrel • NuvaRing
Ethinyl estradiol and norelgestromin • Ortho Evra
Ethinyl estradiol and norgestimate • Ortho Tri-Cyclen, TriNessa, others
Etonogestrel • Implanon, Nexplanon
Gabapentin • Neurontin
Lamotrigine • Lamictal
Levonorgestrel emergency contraceptive pill • AfterPill, Plan B
Levonorgestrel intrauterine device • Mirena, Skyla
Medroxyprogesterone acetate • Depo-Provera
Oxcarbazepine • Trileptal
Topiramate • Topamax
Valproic acid • Depakene

Ms. A, age 20, presents to the clinic after experiencing difficulty sleeping, depressed mood, fatigue, and difficulty concentrating. Her psychiatric history includes bipolar II disorder (BD II), predominantly with depressive episodes. Ms. A’s current medications include a combination of lamotrigine 200 mg/d and bupropion extended-release 450 mg/d, and her symptoms were well maintained until 2 weeks ago. When her psychiatrist performs a medication reconciliation at her medication management appointment, Ms. A indicates she started taking an oral contraceptive, ethinyl estradiol and norgestimate, approximately 1 month ago for management of endometriosis symptoms. She is not currently taking any other medications or supplements.

Lamotrigine is indicated for epilepsy and as maintenance treatment for BD I. It is also used off-label to treat other mood disorders. After oral administration, lamotrigine is rapidly and fully absorbed with a high bioavailability (98%).The principal metabolic pathway is via glucuronic acid conjugation, leading to the major inactive metabolite 2-N-glucuronide. Minor metabolites include 5-N-glucuronide and a 2-N-glucuronide metabolite.¹

Combined oral contraceptives contain an estrogen component, typically ethinyl estradiol, and a progestin component, which varies based on the specific formulation. The metabolism of ethinyl estradiol occurs through cytochrome P450 (CYP)3A4, CYP2C9, sulfation, and glucuronidation. For progestin—the second component of combined oral contraceptives and the lone com­ponent of progestin-only oral contraceptives—metabolism occurs via CYP3A4 and conjugation reactions.² This article focuses on lamotrigine interactions specifically with oral contraceptives, but it is important to note that other formulations of combined hormonal contraceptives, such as the combined contraceptive patch (Ortho Evra) and vaginal ring (NuvaRing), would be expected to interact in the same way as oral formulations.³

Bidirectional interaction

While many antiseizure medications are known to interact with and potentially decrease the efficacy of oral contraceptives (Table 1^3-6), the interactions between lamotrigine and oral contraceptives is uniquely bidirectional. Combined oral contraceptives are thought to interact with lamotrigine primarily via the estrogen component, which causes increased metabolism of lamotrigine through induction of glucuronidation. This drug interaction decreases the plasma concentrations of lamotrigine in the body by up to 2-fold, resulting in an increased risk of seizures or inadequate mood stabilization.¹ This effect on metabolism is very rapid, resulting in decreases in lamotrigine concentrations within 1 week.^4,7 A recent study suggested that certain progestins may also contribute to decreased plasma levels of lamotrigine, but the mechanism for this is unknown (Table 2^3-7).⁸

Clinicians should consider increasing the lamotrigine dose (potentially as much as 2-fold) in a patient who initiates treatment with a combined hormonal contraceptive. Dose increases should not be >50 to 100 mg/d every week.¹ Collect lamotrigine blood levels before starting a hormonal contraceptive and during dose titration. While there is not a well-established therapeutic range for lamotrigine in BD, expert consensus recommends a range of 1 to 6 mcg/mL.⁸

The lamotrigine dose should be decreased if combined hormonal contraceptives are discontinued. Dose decreases should not exceed 25% of the total daily dose per week.¹ Desogestrel, a progestin-only medication, may increase exposure to lamotrigine, but this has not been observed in research with other progestins.^5,9 When starting a progestin-only pill, monitor patients for signs of lamotrigine toxicity (ataxia, diplopia, dizziness) and consider monitoring their blood levels.

An important consideration to note with combined oral contraceptives is the hormone-free interval, also known as the pill-free week. Due to the rapid effect of estrogens, the lamotrigine concentrations have been shown to rise, even double, during this hormone-free interval, so patients should be closely monitored for adverse effects.³ Some recommend use of an extended cycle regimen (with a limited hormone-free interval), or continuous cycle regimen (with no hormone-free interval) to avoid fluctuations in lamotrigine levels.^3,5 Additionally, data suggest that in patients taking lamotrigine and valproate, which inhibits glucuronidation, oral contraceptives do not cause reductions in lamotrigine concentrations.^2,5 In these instances, dose increases of lamotrigine are not needed.

Continue to: The metabolism of ethinyl estradiol...

The metabolism of ethinyl estradiol and progestin are susceptible to CYP3A4 induction and increased glucuronidation. Serum concentrations may be reduced by ≥50% when used concomitantly with CYP enzyme–inducing medications, which could possibly result in subtherapeutic levels and unplanned pregnancy.³ CYP3A4 induction occurs for up to 4 weeks after discontinuation of an enzyme-inducing agent, pointing to the need for alternative or backup contraception during this time.³ Lamotrigine is not a CYP enzyme–inducing medication; it is unlikely to affect the efficacy of oral contraceptives in the same manner as other antiseizure medications. However, a study of lamotrigine and the combined hormonal contraceptive ethinyl estradiol and levonorgestrel demonstrated reduced exposure to levonorgestrel, resulting in breakthrough bleeding.⁵

In a study on the coadministration of lamotrigine and combined oral contraceptives, Sidhu et al⁴ observed a small mean reduction (20%) in progestin concentrations when lamotrigine was used at a dose of 300 mg/d. Although there is no research suggesting decreased effectiveness in preventing pregnancy when lamotrigine is used with combined oral contraceptives, progestin-only oral contraceptives, or progestin implants, additional or alternative contraceptive methods may be considered based on this pharmacokinetic data, particularly in patients who require lamotrigine doses ≥300 mg/d.⁵

CASE CONTINUED

Given when Ms. A started the oral contraceptive, the treatment team determines it is likely that an interaction with lamotrigine is causing her resurgence of depressive symptoms. Her care team decides to titrate the lamotrigine gradually to 300 mg/d, then 400 mg/d if needed, while carefully monitoring for signs of a serious rash. This dosage increase may help Ms. A achieve symptom remission. Monitoring plasma levels may be considered, although it is unknown what plasma level was effective for Ms. A before she started the oral contraceptive. Ms. A would need to be counseled regarding the effect of higher doses of lamotrigine on the effectiveness of the oral contraceptive.

Although it does not appear Ms. A is using the oral contraceptive specifically to prevent pregnancy, the team informs her about the possibility of unintended pregnancy with this medication combination. If Ms. A was also using the medication for this indication, alternative contraceptive options would include medroxyprogesterone acetate, levonorgestrel implants, or an intrauterine device (levonorgestrel or copper, though copper would not be effective for endometriosis symptom management). Ms. A should consult with her gynecologist regarding the most appropriate option for her endometriosis. If the decision is made to discontinue her oral contraceptive in the future, the lamotrigine dose should be decreased to her previously effective dose of 200 mg/d.

Related Resources

• Makino KK, Hatters Friedman S, Amin J. Emergency contraception for psychiatric patients. Current Psychiatry. 2022;21(11):34-39,44-45. doi:10.12788/cp.0300
• MGH Center for Women’s Mental Health. You asked: is there an interaction between lamotrigine and oral contraceptives? September 29, 2015. https://womensmentalhealth.org/posts/you-asked-is-there-an-interaction-between-lamotrigine-andoral-contraceptives/

Drug Brand Names

Bupropion extended-release • Wellbutrin XL
Carbamazepine • Equetro, Tegretol
Desogestrel • Cerazette
Divalproex sodium • Depakote
Ethinyl estradiol and etonogestrel • NuvaRing
Ethinyl estradiol and norelgestromin • Ortho Evra
Ethinyl estradiol and norgestimate • Ortho Tri-Cyclen, TriNessa, others
Etonogestrel • Implanon, Nexplanon
Gabapentin • Neurontin
Lamotrigine • Lamictal
Levonorgestrel emergency contraceptive pill • AfterPill, Plan B
Levonorgestrel intrauterine device • Mirena, Skyla
Medroxyprogesterone acetate • Depo-Provera
Oxcarbazepine • Trileptal
Topiramate • Topamax
Valproic acid • Depakene

Ms. A, age 20, presents to the clinic after experiencing difficulty sleeping, depressed mood, fatigue, and difficulty concentrating. Her psychiatric history includes bipolar II disorder (BD II), predominantly with depressive episodes. Ms. A’s current medications include a combination of lamotrigine 200 mg/d and bupropion extended-release 450 mg/d, and her symptoms were well maintained until 2 weeks ago. When her psychiatrist performs a medication reconciliation at her medication management appointment, Ms. A indicates she started taking an oral contraceptive, ethinyl estradiol and norgestimate, approximately 1 month ago for management of endometriosis symptoms. She is not currently taking any other medications or supplements.

Lamotrigine is indicated for epilepsy and as maintenance treatment for BD I. It is also used off-label to treat other mood disorders. After oral administration, lamotrigine is rapidly and fully absorbed with a high bioavailability (98%).The principal metabolic pathway is via glucuronic acid conjugation, leading to the major inactive metabolite 2-N-glucuronide. Minor metabolites include 5-N-glucuronide and a 2-N-glucuronide metabolite.¹

Combined oral contraceptives contain an estrogen component, typically ethinyl estradiol, and a progestin component, which varies based on the specific formulation. The metabolism of ethinyl estradiol occurs through cytochrome P450 (CYP)3A4, CYP2C9, sulfation, and glucuronidation. For progestin—the second component of combined oral contraceptives and the lone com­ponent of progestin-only oral contraceptives—metabolism occurs via CYP3A4 and conjugation reactions.² This article focuses on lamotrigine interactions specifically with oral contraceptives, but it is important to note that other formulations of combined hormonal contraceptives, such as the combined contraceptive patch (Ortho Evra) and vaginal ring (NuvaRing), would be expected to interact in the same way as oral formulations.³

Bidirectional interaction

While many antiseizure medications are known to interact with and potentially decrease the efficacy of oral contraceptives (Table 1^3-6), the interactions between lamotrigine and oral contraceptives is uniquely bidirectional. Combined oral contraceptives are thought to interact with lamotrigine primarily via the estrogen component, which causes increased metabolism of lamotrigine through induction of glucuronidation. This drug interaction decreases the plasma concentrations of lamotrigine in the body by up to 2-fold, resulting in an increased risk of seizures or inadequate mood stabilization.¹ This effect on metabolism is very rapid, resulting in decreases in lamotrigine concentrations within 1 week.^4,7 A recent study suggested that certain progestins may also contribute to decreased plasma levels of lamotrigine, but the mechanism for this is unknown (Table 2^3-7).⁸

Clinicians should consider increasing the lamotrigine dose (potentially as much as 2-fold) in a patient who initiates treatment with a combined hormonal contraceptive. Dose increases should not be >50 to 100 mg/d every week.¹ Collect lamotrigine blood levels before starting a hormonal contraceptive and during dose titration. While there is not a well-established therapeutic range for lamotrigine in BD, expert consensus recommends a range of 1 to 6 mcg/mL.⁸

The lamotrigine dose should be decreased if combined hormonal contraceptives are discontinued. Dose decreases should not exceed 25% of the total daily dose per week.¹ Desogestrel, a progestin-only medication, may increase exposure to lamotrigine, but this has not been observed in research with other progestins.^5,9 When starting a progestin-only pill, monitor patients for signs of lamotrigine toxicity (ataxia, diplopia, dizziness) and consider monitoring their blood levels.

An important consideration to note with combined oral contraceptives is the hormone-free interval, also known as the pill-free week. Due to the rapid effect of estrogens, the lamotrigine concentrations have been shown to rise, even double, during this hormone-free interval, so patients should be closely monitored for adverse effects.³ Some recommend use of an extended cycle regimen (with a limited hormone-free interval), or continuous cycle regimen (with no hormone-free interval) to avoid fluctuations in lamotrigine levels.^3,5 Additionally, data suggest that in patients taking lamotrigine and valproate, which inhibits glucuronidation, oral contraceptives do not cause reductions in lamotrigine concentrations.^2,5 In these instances, dose increases of lamotrigine are not needed.

Continue to: The metabolism of ethinyl estradiol...

The metabolism of ethinyl estradiol and progestin are susceptible to CYP3A4 induction and increased glucuronidation. Serum concentrations may be reduced by ≥50% when used concomitantly with CYP enzyme–inducing medications, which could possibly result in subtherapeutic levels and unplanned pregnancy.³ CYP3A4 induction occurs for up to 4 weeks after discontinuation of an enzyme-inducing agent, pointing to the need for alternative or backup contraception during this time.³ Lamotrigine is not a CYP enzyme–inducing medication; it is unlikely to affect the efficacy of oral contraceptives in the same manner as other antiseizure medications. However, a study of lamotrigine and the combined hormonal contraceptive ethinyl estradiol and levonorgestrel demonstrated reduced exposure to levonorgestrel, resulting in breakthrough bleeding.⁵

In a study on the coadministration of lamotrigine and combined oral contraceptives, Sidhu et al⁴ observed a small mean reduction (20%) in progestin concentrations when lamotrigine was used at a dose of 300 mg/d. Although there is no research suggesting decreased effectiveness in preventing pregnancy when lamotrigine is used with combined oral contraceptives, progestin-only oral contraceptives, or progestin implants, additional or alternative contraceptive methods may be considered based on this pharmacokinetic data, particularly in patients who require lamotrigine doses ≥300 mg/d.⁵

CASE CONTINUED

Given when Ms. A started the oral contraceptive, the treatment team determines it is likely that an interaction with lamotrigine is causing her resurgence of depressive symptoms. Her care team decides to titrate the lamotrigine gradually to 300 mg/d, then 400 mg/d if needed, while carefully monitoring for signs of a serious rash. This dosage increase may help Ms. A achieve symptom remission. Monitoring plasma levels may be considered, although it is unknown what plasma level was effective for Ms. A before she started the oral contraceptive. Ms. A would need to be counseled regarding the effect of higher doses of lamotrigine on the effectiveness of the oral contraceptive.

Although it does not appear Ms. A is using the oral contraceptive specifically to prevent pregnancy, the team informs her about the possibility of unintended pregnancy with this medication combination. If Ms. A was also using the medication for this indication, alternative contraceptive options would include medroxyprogesterone acetate, levonorgestrel implants, or an intrauterine device (levonorgestrel or copper, though copper would not be effective for endometriosis symptom management). Ms. A should consult with her gynecologist regarding the most appropriate option for her endometriosis. If the decision is made to discontinue her oral contraceptive in the future, the lamotrigine dose should be decreased to her previously effective dose of 200 mg/d.

Related Resources

• Makino KK, Hatters Friedman S, Amin J. Emergency contraception for psychiatric patients. Current Psychiatry. 2022;21(11):34-39,44-45. doi:10.12788/cp.0300
• MGH Center for Women’s Mental Health. You asked: is there an interaction between lamotrigine and oral contraceptives? September 29, 2015. https://womensmentalhealth.org/posts/you-asked-is-there-an-interaction-between-lamotrigine-andoral-contraceptives/

Drug Brand Names

Bupropion extended-release • Wellbutrin XL
Carbamazepine • Equetro, Tegretol
Desogestrel • Cerazette
Divalproex sodium • Depakote
Ethinyl estradiol and etonogestrel • NuvaRing
Ethinyl estradiol and norelgestromin • Ortho Evra
Ethinyl estradiol and norgestimate • Ortho Tri-Cyclen, TriNessa, others
Etonogestrel • Implanon, Nexplanon
Gabapentin • Neurontin
Lamotrigine • Lamictal
Levonorgestrel emergency contraceptive pill • AfterPill, Plan B
Levonorgestrel intrauterine device • Mirena, Skyla
Medroxyprogesterone acetate • Depo-Provera
Oxcarbazepine • Trileptal
Topiramate • Topamax
Valproic acid • Depakene

Although the guidelines for masking in hospitals and other health care settings have been revised and face masks are no longer mandatory, it is important to note that some patients and clinicians will choose to continue wearing masks for various personal or clinical reasons. While effective in reducing transmission of the coronavirus, masks have created challenges in assessing patients’ affective states, which impacts the accuracy of diagnosis and treatment. This article discusses strategies for assessing affect in patients wearing face masks.

How masks complicate assessing affect

One obvious challenge masks present is they prevent clinicians from seeing their patients’ facial expressions. Face masks cover the mouth, nose, and cheeks, all of which are involved in communicating emotions. As a result, clinicians may miss important cues that could inform their assessment of a patient’s affect. For example, when a masked patient is smiling, it is difficult to determine whether their smile is genuine or forced. A study that evaluated the interpretation of 6 emotions (angry, disgusted, fearful, happy, neutral, and sad) in masked patients found that emotion recognition was significantly reduced for all emotions except for fearful and neutral faces.¹

Another challenge is the potential for misinterpretation. Health care professionals may rely more heavily on nonverbal cues, such as body language, to interpret a patient’s affect. However, these cues can be influenced by other factors, such as cultural differences and individual variations in communication style. Culture is a key component in assessing nonverbal emotion reading cues.²

Strategies to overcome these challenges

There are several strategies clinicians can use to overcome the difficulties of assessing affect while a patient is wearing a mask:

Focus on other nonverbal cues, such as a patient’s posture and hand gestures. Verbal cues—such as tone of voice, choice of words, and voice inflection—can also provide valuable insights. For example, a patient who speaks in a hesitant or monotone voice may be experiencing anxiety or depression. Clinicians can ask open-ended questions, encouraging patients to expand on their emotions and provide further information about their affect.

Maintain eye contact. Eye contact is an essential component of nonverbal communication. The eyes are “the window of the soul” and can convey various emotions including happiness, sadness, fear, anger, surprise, trust, interest, and empathy. Maintaining eye contact is crucial for building positive relationships with patients, and learning to smile with your eyes (smize) can help build rapport.

Take advantage of technology. Clinicians can leverage telemedicine to assess affect. Telemedicine platforms, which have become increasingly popular during the COVID-19 pandemic, allow clinicians to monitor patients remotely and observe nonverbal cues. Virtual reality technology can also help by documenting physiological responses such as heart rate and skin conductance.

Use standardized assessment tools, as these instruments can aid in assessing affect. For example, the Patient Health Questionnaire-9 and Generalized Anxiety Disorder 7-item scale are standardized questionnaires assessing depression and anxiety, respectively. Administering these tools to patients wearing a face mask can provide information about their affective state.

Although the guidelines for masking in hospitals and other health care settings have been revised and face masks are no longer mandatory, it is important to note that some patients and clinicians will choose to continue wearing masks for various personal or clinical reasons. While effective in reducing transmission of the coronavirus, masks have created challenges in assessing patients’ affective states, which impacts the accuracy of diagnosis and treatment. This article discusses strategies for assessing affect in patients wearing face masks.

How masks complicate assessing affect

One obvious challenge masks present is they prevent clinicians from seeing their patients’ facial expressions. Face masks cover the mouth, nose, and cheeks, all of which are involved in communicating emotions. As a result, clinicians may miss important cues that could inform their assessment of a patient’s affect. For example, when a masked patient is smiling, it is difficult to determine whether their smile is genuine or forced. A study that evaluated the interpretation of 6 emotions (angry, disgusted, fearful, happy, neutral, and sad) in masked patients found that emotion recognition was significantly reduced for all emotions except for fearful and neutral faces.¹

Another challenge is the potential for misinterpretation. Health care professionals may rely more heavily on nonverbal cues, such as body language, to interpret a patient’s affect. However, these cues can be influenced by other factors, such as cultural differences and individual variations in communication style. Culture is a key component in assessing nonverbal emotion reading cues.²

Strategies to overcome these challenges

There are several strategies clinicians can use to overcome the difficulties of assessing affect while a patient is wearing a mask:

Focus on other nonverbal cues, such as a patient’s posture and hand gestures. Verbal cues—such as tone of voice, choice of words, and voice inflection—can also provide valuable insights. For example, a patient who speaks in a hesitant or monotone voice may be experiencing anxiety or depression. Clinicians can ask open-ended questions, encouraging patients to expand on their emotions and provide further information about their affect.

Maintain eye contact. Eye contact is an essential component of nonverbal communication. The eyes are “the window of the soul” and can convey various emotions including happiness, sadness, fear, anger, surprise, trust, interest, and empathy. Maintaining eye contact is crucial for building positive relationships with patients, and learning to smile with your eyes (smize) can help build rapport.

Take advantage of technology. Clinicians can leverage telemedicine to assess affect. Telemedicine platforms, which have become increasingly popular during the COVID-19 pandemic, allow clinicians to monitor patients remotely and observe nonverbal cues. Virtual reality technology can also help by documenting physiological responses such as heart rate and skin conductance.

Use standardized assessment tools, as these instruments can aid in assessing affect. For example, the Patient Health Questionnaire-9 and Generalized Anxiety Disorder 7-item scale are standardized questionnaires assessing depression and anxiety, respectively. Administering these tools to patients wearing a face mask can provide information about their affective state.

Although the guidelines for masking in hospitals and other health care settings have been revised and face masks are no longer mandatory, it is important to note that some patients and clinicians will choose to continue wearing masks for various personal or clinical reasons. While effective in reducing transmission of the coronavirus, masks have created challenges in assessing patients’ affective states, which impacts the accuracy of diagnosis and treatment. This article discusses strategies for assessing affect in patients wearing face masks.

How masks complicate assessing affect

One obvious challenge masks present is they prevent clinicians from seeing their patients’ facial expressions. Face masks cover the mouth, nose, and cheeks, all of which are involved in communicating emotions. As a result, clinicians may miss important cues that could inform their assessment of a patient’s affect. For example, when a masked patient is smiling, it is difficult to determine whether their smile is genuine or forced. A study that evaluated the interpretation of 6 emotions (angry, disgusted, fearful, happy, neutral, and sad) in masked patients found that emotion recognition was significantly reduced for all emotions except for fearful and neutral faces.¹

Another challenge is the potential for misinterpretation. Health care professionals may rely more heavily on nonverbal cues, such as body language, to interpret a patient’s affect. However, these cues can be influenced by other factors, such as cultural differences and individual variations in communication style. Culture is a key component in assessing nonverbal emotion reading cues.²

Strategies to overcome these challenges

There are several strategies clinicians can use to overcome the difficulties of assessing affect while a patient is wearing a mask:

Focus on other nonverbal cues, such as a patient’s posture and hand gestures. Verbal cues—such as tone of voice, choice of words, and voice inflection—can also provide valuable insights. For example, a patient who speaks in a hesitant or monotone voice may be experiencing anxiety or depression. Clinicians can ask open-ended questions, encouraging patients to expand on their emotions and provide further information about their affect.

Maintain eye contact. Eye contact is an essential component of nonverbal communication. The eyes are “the window of the soul” and can convey various emotions including happiness, sadness, fear, anger, surprise, trust, interest, and empathy. Maintaining eye contact is crucial for building positive relationships with patients, and learning to smile with your eyes (smize) can help build rapport.

Take advantage of technology. Clinicians can leverage telemedicine to assess affect. Telemedicine platforms, which have become increasingly popular during the COVID-19 pandemic, allow clinicians to monitor patients remotely and observe nonverbal cues. Virtual reality technology can also help by documenting physiological responses such as heart rate and skin conductance.

Use standardized assessment tools, as these instruments can aid in assessing affect. For example, the Patient Health Questionnaire-9 and Generalized Anxiety Disorder 7-item scale are standardized questionnaires assessing depression and anxiety, respectively. Administering these tools to patients wearing a face mask can provide information about their affective state.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].

As an emergency department (ED) psychiatrist with 25 years of experience working in a large city, I am growing increasingly concerned about the escalating number of individuals experiencing homelessness in urban areas.

Homelessness remains a critical issue across the United States. The news reports from major urban areas are startling. In my own practice, I encounter approximately 10,000 patients annually, and at least one-half of them are homeless. Additionally, 75% of these patients who are homeless experience addiction, and many have lost all social support. Due to overcrowding at our area’s shelters, they resort to using the ED as a shelter because most of our shelters are overcrowded. This situation has caused an overwhelming overload in the ED and left staff disheartened and difficult to retain.

The relationship between mental illness and homelessness is complex and multifaceted. Research suggests that up to one-third of individuals who are homeless have serious mental illness.¹ Mental illness can contribute to homelessness by impeding individuals’ ability to maintain employment, housing, and social relationships. Conversely, homelessness can worsen mental illness (especially in younger individuals, who are most vulnerable) by exposing individuals to traumatic experiences, substance abuse, and other stressors.²

One approach to effectively address homelessness in urban areas is provide supportive housing that incorporates access to mental health services. Research has demonstrated that offering stable housing and mental health services to individuals experiencing homelessness can significantly improve their mental and physical health and reduce their reliance on costly emergency services.^3,4

Collaboration between the health care system and government is also essential. By working together, the health care system and government can develop comprehensive strategies, allocate resources, and implement interventions that address the physical and mental health needs of individuals who are homeless and provide them with the necessary support and services. This collaboration is essential to create sustainable solutions and make a meaningful impact in combating homelessness.⁵

Addressing homelessness in urban areas requires a comprehensive approach that recognizes the critical role of mental illness and necessity for collaborative solutions. While our ED has implemented certain measures, such as allowing patients to remain on 23-hour holds to prevent immediate re-admission, additional interventions are needed. These include expanding shelters and transitional housing programs, which are currently in short supply, and developing street medicine programs to meet individuals where they are and improve compliance with medications. By implementing these strategies, we can help minimize the impact of homelessness on individuals with mental illness and enhance the health and well-being of individuals experiencing homelessness.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].

As an emergency department (ED) psychiatrist with 25 years of experience working in a large city, I am growing increasingly concerned about the escalating number of individuals experiencing homelessness in urban areas.

Homelessness remains a critical issue across the United States. The news reports from major urban areas are startling. In my own practice, I encounter approximately 10,000 patients annually, and at least one-half of them are homeless. Additionally, 75% of these patients who are homeless experience addiction, and many have lost all social support. Due to overcrowding at our area’s shelters, they resort to using the ED as a shelter because most of our shelters are overcrowded. This situation has caused an overwhelming overload in the ED and left staff disheartened and difficult to retain.

The relationship between mental illness and homelessness is complex and multifaceted. Research suggests that up to one-third of individuals who are homeless have serious mental illness.¹ Mental illness can contribute to homelessness by impeding individuals’ ability to maintain employment, housing, and social relationships. Conversely, homelessness can worsen mental illness (especially in younger individuals, who are most vulnerable) by exposing individuals to traumatic experiences, substance abuse, and other stressors.²

One approach to effectively address homelessness in urban areas is provide supportive housing that incorporates access to mental health services. Research has demonstrated that offering stable housing and mental health services to individuals experiencing homelessness can significantly improve their mental and physical health and reduce their reliance on costly emergency services.^3,4

Collaboration between the health care system and government is also essential. By working together, the health care system and government can develop comprehensive strategies, allocate resources, and implement interventions that address the physical and mental health needs of individuals who are homeless and provide them with the necessary support and services. This collaboration is essential to create sustainable solutions and make a meaningful impact in combating homelessness.⁵

Addressing homelessness in urban areas requires a comprehensive approach that recognizes the critical role of mental illness and necessity for collaborative solutions. While our ED has implemented certain measures, such as allowing patients to remain on 23-hour holds to prevent immediate re-admission, additional interventions are needed. These include expanding shelters and transitional housing programs, which are currently in short supply, and developing street medicine programs to meet individuals where they are and improve compliance with medications. By implementing these strategies, we can help minimize the impact of homelessness on individuals with mental illness and enhance the health and well-being of individuals experiencing homelessness.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].

As an emergency department (ED) psychiatrist with 25 years of experience working in a large city, I am growing increasingly concerned about the escalating number of individuals experiencing homelessness in urban areas.

Homelessness remains a critical issue across the United States. The news reports from major urban areas are startling. In my own practice, I encounter approximately 10,000 patients annually, and at least one-half of them are homeless. Additionally, 75% of these patients who are homeless experience addiction, and many have lost all social support. Due to overcrowding at our area’s shelters, they resort to using the ED as a shelter because most of our shelters are overcrowded. This situation has caused an overwhelming overload in the ED and left staff disheartened and difficult to retain.

The relationship between mental illness and homelessness is complex and multifaceted. Research suggests that up to one-third of individuals who are homeless have serious mental illness.¹ Mental illness can contribute to homelessness by impeding individuals’ ability to maintain employment, housing, and social relationships. Conversely, homelessness can worsen mental illness (especially in younger individuals, who are most vulnerable) by exposing individuals to traumatic experiences, substance abuse, and other stressors.²

One approach to effectively address homelessness in urban areas is provide supportive housing that incorporates access to mental health services. Research has demonstrated that offering stable housing and mental health services to individuals experiencing homelessness can significantly improve their mental and physical health and reduce their reliance on costly emergency services.^3,4

Collaboration between the health care system and government is also essential. By working together, the health care system and government can develop comprehensive strategies, allocate resources, and implement interventions that address the physical and mental health needs of individuals who are homeless and provide them with the necessary support and services. This collaboration is essential to create sustainable solutions and make a meaningful impact in combating homelessness.⁵

Addressing homelessness in urban areas requires a comprehensive approach that recognizes the critical role of mental illness and necessity for collaborative solutions. While our ED has implemented certain measures, such as allowing patients to remain on 23-hour holds to prevent immediate re-admission, additional interventions are needed. These include expanding shelters and transitional housing programs, which are currently in short supply, and developing street medicine programs to meet individuals where they are and improve compliance with medications. By implementing these strategies, we can help minimize the impact of homelessness on individuals with mental illness and enhance the health and well-being of individuals experiencing homelessness.

More on an asymmetric life

I enjoy receiving Current Psychiatry each month and read Dr. Nasrallah's editorials with great interest, as there is often an interesting angle to the topic. However, I found your recent editorial (“The joys and rewards of an asymmetric life,” Current Psychiatry, May 2023, p. 7-8,16, doi:10.12788/cp.0361) perplexing. You and I (and most male physicians) have certainly been privileged, but not everyone gets to lead an asymmetric life. For many of our patients, an unbalanced life is part and parcel of their mental illness.

Too often, families bear the burden of an individual’s hyperfocused pursuits. I hope your wife has been able to pursue her occupation with the same zeal and commitment. We have all read biographies of driven individuals and, unfortunately, someone pays the price for another’s success. For every Steve Jobs, there is a Lisa Jobs.

If we were surgeons, I would applaud your essay. However, we are psychiatrists. If anything, we balance out the reductionist forces in medicine. When every other physician claims a cure with medications or procedures, we look at all aspects of the patient’s life to find the appropriate treatment. At least that’s what we should be doing.

I was part of the first class of residents to work under the 80-hours-per-week restrictions. I was grateful for the extra time to rest, exercise, and spend time with my wife. The 80-hour restrictions improved resident wellness and had no impact on patient care. There are intangible benefits of diverting the mind from a chosen pursuit (such as creativity).

There is no doubt that becoming number 1 in any field requires a tremendous amount of determination, sacrifice, and effort. But not everyone gets to be first. Our society’s single-minded focus on being the best has had a major impact on mental health, especially for children. I hope you can address that in a future editorial.

Sudhir Nagaraja, DO, MS
Fredericksburg, Virginia

Dr. Nasrallah responds

Thank you for your letter about my editorial. You obviously believe in leading a balanced life, and that’s fine if you so choose. I described why I decided at an early age to lead an intensive, “purpose-driven life,” which requires investing much more time than others do, to achieve my lofty goals and excel in my area of expertise (academic psychiatry). It is really a “calling,” and those who score an extraordinary achievement (a moonshot) in their life, including Olympic gold medalists, entrepreneurs, inventors, or Nobel laureates, must do exactly what I do. I am not urging anyone to do what I have chosen to do in my life. Everyone defines for themselves what constitutes the pursuit of happiness.

You mentioned my wife. Let me assert that she is highly successful as a mother and as a research psychologist. She is my extremely valuable life partner and very supportive of what I do. I am fortunate to have chosen well!

Continue to: More on transient global amnesia

Your recent article on transient global amnesia (TGA) (“Transient global amnesia: Psychiatric precipitants, features, and comorbidities,” Current Psychiatry, April 2023, p. 30-35,40, doi:10.12788/cp.0345) is an encouragement for psychiatrists to bring their skills to explore disorders often seen as the primary task of neurology. The article presents a woman with a history of trauma who received a severe emotional shock that triggered TGA. The discussion of a proposed treatment (lorazepam) brings a psychopharmacologic focus to TGA.

I witnessed TGA, experienced by my brother, while on a surf trip. After bodyboarding for about an hour in cold water, wearing a full wet suit and hood, he met me on the beach. He recognized me and knew my name but had no idea where we were, how we got there, or other events from earlier that morning. There was no stressor, just the usual surfing excitement. We went to a local emergency department, where the physical examination, usual laboratory tests, and neuroimaging were normal. After approximately 5 hours, he began to fully recall recent events. Ten years later, there has been no recurrence. The only change in his surfing habits has been to avoid using a hood with neck coverage.

In 2022, Papadis et al¹ described a case of concurrent Takotsubo cardio­myopathy and TGA, noting that cardiovascular dysfunction and neuro­logic dysfunction may be provoked by an emotional or stressful situation. The interesting observations of capture myopathy from animal literature appear similar to human reactions to trauma.^1-3

Case reports of scopolamine intoxication have been linked to TGA. Severe memory disturbances, characteristics of dry mouth, blurred vision, and tachycardia were evident. Certain South American plant extracts popularly known as “Burundanga” have anticholinergic effects. Severe anterograde amnesia and submissiveness represent the 2 most notorious clinical signs of Burundanga intoxication.⁴

As one reviews single and groups of case studies, several things stand out. The hallmark of TGA is the sudden inability to make new memories, which resolves in a few hours. The brief and isolated dysfunction is what distinguishes this condition from most episodic disorders, but a clinician should not prognosticate too much without screening for ischemic or metabolic disturbance. Common associated precursors include Valsalva-associated activities, emotional stress with anxiety, acute pain, cold water immersion, static neck posture, and age older than 55.^5,6 

Neuropsychiatric disorders involve the neuron and its connections. Major reflexes automate the processes of the “neurocardiac” axis. The vasovagal reflex (Barcroft/Edholm reflex), diving reflex, baroreceptor reflex, Cushing reflex, and others depend upon the conversion of a mechanical stimulus to neurotransmission. The reflexes have sensors, afferent paths, a central processing, and efferent paths that lead to events or experiences. CNS processing is complex but the brainstem, amygdala, prefrontal cortex, and some cortical regions are involved. Neurocardiac reactions can come from pathologic events, including ischemia, metabolic disturbance, pain signals, or emotional effects within the axis.^7-11

Understanding neurocardiac reflexes may help our progress with challenging clinical conditions, such as chronic pain, trauma, and cognitive impairment. The broad use of vagus nerve stimulation is one indicator of the power of this focus.^12-19 Lewis²⁰ suggested increased susceptibility to retrograde jugular venous flow could cause regional brain ischemia, resulting in TGA. The competency of jugular venous valves during the Valsalva maneuver could be assessed with Doppler ultrasound. Abnormalities could be managed, and results assessed.^20,21 Vascular shunting from memory regions in the brain to essential neurocardiac control areas should be considered.

Cholinergic processes are active in the parasympathetic nervous system, sustained attention, working memory, executive functions, and mood. Increased central cholinergic activity may lead to depression. Scopolamine, in its therapeutic range, has antidepressant effects but in toxic doses is a dissociative agent.^22,23 While cholinesterase inhibitors are used in Alzheimer disease, cholinergic agonists have yet to play a large role in general psychiatry or functional neurology.

TGA continues to provide a window into memory, functional disorders, psychological defenses, and adaptive neurocardiac processes. Continued clinical care and research might include gradual adaptation to cold water immersion, caution with the Valsalva maneuver, cholinergic support, managing the trapped response, avoiding interference with normal jugular flow, and evaluation for jugular venous insufficiency.

Because a variety of medical procedures can trigger TGA, health care professionals in many fields need to understand this symptom complex.^24-27 Thanks to the authors for raising the awareness of TGA for psychiatrists.

Mark Chandler, MD
Durham, North Carolina

References

1. Papadis A, Svab S, Brugger N, et al. “Broken heart” and “broken brain”: which connection? Cardiol Res. 2022;13(1):65-70. doi:10.14740/cr1336

2. Blumstein DT, Buckner J, Shah S, et al. The evolution of capture myopathy in hooved mammals: a model for human stress cardiomyopathy? Evol Med Public Health. 2015;2015(1):195-203. doi:10.1093/emph/eov015

3. Seguel M, Paredes E, Pavés H, et al. Capture-induced stress cardiomyopathy in South American fur seal pups (Arctophoca australis gracilis). Marine Mammal Science. 2014;30(3): 1149-1157. https://doi.org/10.1111/mms.12079

4. Ardila A, Moreno C. Scopolamine intoxication as a model of transient global amnesia. Brain Cogn. 1991;15(2):236-245. doi:10.1016/0278-2626(91)90028-7

5. Bartsch T, Deuschl G. Transient global amnesia: functional anatomy and clinical implications. Lancet Neurol. 2010;9(2):205-214. doi:10.1016/S1474-4422(09)70344-8

6. Spiegel DR, Smith J, Wade RR, et al. Transient global amnesia: current perspectives. Neuropsychiatr Dis Treat. 2017;13:2691-2703. doi:10.2147/NDT.S130710

7. Yartsev A. Cardiac reflexes. August 15, 2020. Updated May 19, 2023. Accessed June 12, 2023. https://derangedphysiology.com/main/cicm-primary-exam/required-reading/cardiovascular-system/Chapter%20491/cardiac-reflexes

8. Lemaitre F, Chowdhury T, Schaller B. The trigeminocardiac reflex - a comparison with the diving reflex in humans. Arch Med Sci. 2015;11(2):419-426. doi:10.5114/aoms.2015.50974

9. Lindholm P, Lundgren CE. The physiology and pathophysiology of human breath-hold diving. J Appl Physiol (1985). 2009;106(1):284-292. doi:10.1152/japplphysiol.90991.2008

10. Tansey EA, Johnson CD. Recent advances in thermoregulation. Adv Physiol Educ. 2015;39(3):139-148. doi:10.1152/advan.00126.2014

11. Alboni P, Alboni M. Vasovagal syncope as a manifestation of an evolutionary selected trait. J Atr Fibrillation. 2014;7(2):1035. doi:10.4022/jafib.1035

12. Badran BW, Austelle CW. The future is noninvasive: a brief review of the evolution and clinical utility of vagus nerve stimulation. Focus (Am Psychiatr Publ). 2022;20(1):3-7. doi:10.1176/appi.focus.20210023

13. Suarez-Roca H, Mamoun N, Sigurdson MI, et al. Baroreceptor modulation of the cardiovascular system, pain, consciousness, and cognition. Compr Physiol. 2021;11(2):1373-1423. doi:10.1002/cphy.c190038

14. Pinna T, Edwards DJ. A systematic review of associations between interoception, vagal tone, and emotional regulation: potential applications for mental health, wellbeing, psychological flexibility, and chronic conditions. Front Psychol. 2020;11:1792. doi:10.3389/fpsyg.2020.01792

15. Howland RH. Vagus nerve stimulation. Curr Behav Neurosci Rep. 2014 Jun;1(2):64-73. doi:10.1007/s40473-014-0010-5

16. Panneton WM, Gan Q. The mammalian diving response: inroads to its neural control. Front Neurosci. 2020;14:524. doi:10.3389/fnins.2020.00524

17. Khurana RK, Wu R. The cold face test: a non-baroreflex mediated test of cardiac vagal function. Clin Auton Res. 2006;16(3):202-207. doi:10.1007/s10286-006-0332-9

18. Montirosso R, Provenzi L, Tronick E, et al. Vagal tone as a biomarker of long-term memory for a stressful social event at 4 months. Dev Psychobiol. 2014;56(7):1564-1574. doi:10.1002/dev.21251

19. Hansen AL, Johnsen BH, Thayer JF. Vagal influence on working memory and attention. Int J Psychophysiol. 2003;48(3):263-274. doi:10.1016/s0167-8760(03)00073-4

20. Lewis SL. Aetiology of transient global amnesia. Lancet. 1998;352(9125):397-399. doi:10.1016/S0140-6736(98)01442-1

21. Han K, Chao AC, Chang FC, et al. Obstruction of venous drainage linked to transient global amnesia. PLoS One. 2015;10(7):e0132893. doi:10.1371/journal.pone.0132893

22. Picciotto MR, Higley MJ, Mineur YS. Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron. 2012;76(1):116-129. doi:10.1016/j.neuron.2012.08.036

23. Dulawa SC, Janowsky DS. Cholinergic regulation of mood: from basic and clinical studies to emerging therapeutics. Mol Psychiatry. 2019;24(5):694-709. doi:10.1038/s41380-018-0219-x

24. Grande LA, Loeser JD, Samii A. Recurrent transient global amnesia with intrathecal baclofen. Anesth Analg. 2008;106(4):1284-1287. doi:10.1213/ane.0b013e318165e1c6

25. Carrard J, Lambert AC, Genné D. Transient global amnesia following a whole-body cryotherapy session. BMJ Case Rep. 2017;2017:bcr2017221431. doi:10.1136/bcr-2017-221431

26. Jeong M, Kim WS, Kim AR, et al. Medical procedure-related transient global amnesia. Eur Neurol. 2018;80(1-2):42-49. doi:10.1159/000493163

27. Shah B, Hussain MW. Concussion causing transient global amnesia: further insights into pathophysiology? Neurology. 2020;95(20 Suppl 1):S16. doi:10.1212/01.wnl.0000720020.86134.9d

More on an asymmetric life

I enjoy receiving Current Psychiatry each month and read Dr. Nasrallah's editorials with great interest, as there is often an interesting angle to the topic. However, I found your recent editorial (“The joys and rewards of an asymmetric life,” Current Psychiatry, May 2023, p. 7-8,16, doi:10.12788/cp.0361) perplexing. You and I (and most male physicians) have certainly been privileged, but not everyone gets to lead an asymmetric life. For many of our patients, an unbalanced life is part and parcel of their mental illness.

Too often, families bear the burden of an individual’s hyperfocused pursuits. I hope your wife has been able to pursue her occupation with the same zeal and commitment. We have all read biographies of driven individuals and, unfortunately, someone pays the price for another’s success. For every Steve Jobs, there is a Lisa Jobs.

If we were surgeons, I would applaud your essay. However, we are psychiatrists. If anything, we balance out the reductionist forces in medicine. When every other physician claims a cure with medications or procedures, we look at all aspects of the patient’s life to find the appropriate treatment. At least that’s what we should be doing.

I was part of the first class of residents to work under the 80-hours-per-week restrictions. I was grateful for the extra time to rest, exercise, and spend time with my wife. The 80-hour restrictions improved resident wellness and had no impact on patient care. There are intangible benefits of diverting the mind from a chosen pursuit (such as creativity).

There is no doubt that becoming number 1 in any field requires a tremendous amount of determination, sacrifice, and effort. But not everyone gets to be first. Our society’s single-minded focus on being the best has had a major impact on mental health, especially for children. I hope you can address that in a future editorial.

Sudhir Nagaraja, DO, MS
Fredericksburg, Virginia

Dr. Nasrallah responds

Thank you for your letter about my editorial. You obviously believe in leading a balanced life, and that’s fine if you so choose. I described why I decided at an early age to lead an intensive, “purpose-driven life,” which requires investing much more time than others do, to achieve my lofty goals and excel in my area of expertise (academic psychiatry). It is really a “calling,” and those who score an extraordinary achievement (a moonshot) in their life, including Olympic gold medalists, entrepreneurs, inventors, or Nobel laureates, must do exactly what I do. I am not urging anyone to do what I have chosen to do in my life. Everyone defines for themselves what constitutes the pursuit of happiness.

You mentioned my wife. Let me assert that she is highly successful as a mother and as a research psychologist. She is my extremely valuable life partner and very supportive of what I do. I am fortunate to have chosen well!

Continue to: More on transient global amnesia

Your recent article on transient global amnesia (TGA) (“Transient global amnesia: Psychiatric precipitants, features, and comorbidities,” Current Psychiatry, April 2023, p. 30-35,40, doi:10.12788/cp.0345) is an encouragement for psychiatrists to bring their skills to explore disorders often seen as the primary task of neurology. The article presents a woman with a history of trauma who received a severe emotional shock that triggered TGA. The discussion of a proposed treatment (lorazepam) brings a psychopharmacologic focus to TGA.

I witnessed TGA, experienced by my brother, while on a surf trip. After bodyboarding for about an hour in cold water, wearing a full wet suit and hood, he met me on the beach. He recognized me and knew my name but had no idea where we were, how we got there, or other events from earlier that morning. There was no stressor, just the usual surfing excitement. We went to a local emergency department, where the physical examination, usual laboratory tests, and neuroimaging were normal. After approximately 5 hours, he began to fully recall recent events. Ten years later, there has been no recurrence. The only change in his surfing habits has been to avoid using a hood with neck coverage.

In 2022, Papadis et al¹ described a case of concurrent Takotsubo cardio­myopathy and TGA, noting that cardiovascular dysfunction and neuro­logic dysfunction may be provoked by an emotional or stressful situation. The interesting observations of capture myopathy from animal literature appear similar to human reactions to trauma.^1-3

Case reports of scopolamine intoxication have been linked to TGA. Severe memory disturbances, characteristics of dry mouth, blurred vision, and tachycardia were evident. Certain South American plant extracts popularly known as “Burundanga” have anticholinergic effects. Severe anterograde amnesia and submissiveness represent the 2 most notorious clinical signs of Burundanga intoxication.⁴

As one reviews single and groups of case studies, several things stand out. The hallmark of TGA is the sudden inability to make new memories, which resolves in a few hours. The brief and isolated dysfunction is what distinguishes this condition from most episodic disorders, but a clinician should not prognosticate too much without screening for ischemic or metabolic disturbance. Common associated precursors include Valsalva-associated activities, emotional stress with anxiety, acute pain, cold water immersion, static neck posture, and age older than 55.^5,6 

Neuropsychiatric disorders involve the neuron and its connections. Major reflexes automate the processes of the “neurocardiac” axis. The vasovagal reflex (Barcroft/Edholm reflex), diving reflex, baroreceptor reflex, Cushing reflex, and others depend upon the conversion of a mechanical stimulus to neurotransmission. The reflexes have sensors, afferent paths, a central processing, and efferent paths that lead to events or experiences. CNS processing is complex but the brainstem, amygdala, prefrontal cortex, and some cortical regions are involved. Neurocardiac reactions can come from pathologic events, including ischemia, metabolic disturbance, pain signals, or emotional effects within the axis.^7-11

Understanding neurocardiac reflexes may help our progress with challenging clinical conditions, such as chronic pain, trauma, and cognitive impairment. The broad use of vagus nerve stimulation is one indicator of the power of this focus.^12-19 Lewis²⁰ suggested increased susceptibility to retrograde jugular venous flow could cause regional brain ischemia, resulting in TGA. The competency of jugular venous valves during the Valsalva maneuver could be assessed with Doppler ultrasound. Abnormalities could be managed, and results assessed.^20,21 Vascular shunting from memory regions in the brain to essential neurocardiac control areas should be considered.

Cholinergic processes are active in the parasympathetic nervous system, sustained attention, working memory, executive functions, and mood. Increased central cholinergic activity may lead to depression. Scopolamine, in its therapeutic range, has antidepressant effects but in toxic doses is a dissociative agent.^22,23 While cholinesterase inhibitors are used in Alzheimer disease, cholinergic agonists have yet to play a large role in general psychiatry or functional neurology.

TGA continues to provide a window into memory, functional disorders, psychological defenses, and adaptive neurocardiac processes. Continued clinical care and research might include gradual adaptation to cold water immersion, caution with the Valsalva maneuver, cholinergic support, managing the trapped response, avoiding interference with normal jugular flow, and evaluation for jugular venous insufficiency.

Because a variety of medical procedures can trigger TGA, health care professionals in many fields need to understand this symptom complex.^24-27 Thanks to the authors for raising the awareness of TGA for psychiatrists.

Mark Chandler, MD
Durham, North Carolina

References

1. Papadis A, Svab S, Brugger N, et al. “Broken heart” and “broken brain”: which connection? Cardiol Res. 2022;13(1):65-70. doi:10.14740/cr1336

2. Blumstein DT, Buckner J, Shah S, et al. The evolution of capture myopathy in hooved mammals: a model for human stress cardiomyopathy? Evol Med Public Health. 2015;2015(1):195-203. doi:10.1093/emph/eov015

3. Seguel M, Paredes E, Pavés H, et al. Capture-induced stress cardiomyopathy in South American fur seal pups (Arctophoca australis gracilis). Marine Mammal Science. 2014;30(3): 1149-1157. https://doi.org/10.1111/mms.12079

4. Ardila A, Moreno C. Scopolamine intoxication as a model of transient global amnesia. Brain Cogn. 1991;15(2):236-245. doi:10.1016/0278-2626(91)90028-7

5. Bartsch T, Deuschl G. Transient global amnesia: functional anatomy and clinical implications. Lancet Neurol. 2010;9(2):205-214. doi:10.1016/S1474-4422(09)70344-8

6. Spiegel DR, Smith J, Wade RR, et al. Transient global amnesia: current perspectives. Neuropsychiatr Dis Treat. 2017;13:2691-2703. doi:10.2147/NDT.S130710

7. Yartsev A. Cardiac reflexes. August 15, 2020. Updated May 19, 2023. Accessed June 12, 2023. https://derangedphysiology.com/main/cicm-primary-exam/required-reading/cardiovascular-system/Chapter%20491/cardiac-reflexes

8. Lemaitre F, Chowdhury T, Schaller B. The trigeminocardiac reflex - a comparison with the diving reflex in humans. Arch Med Sci. 2015;11(2):419-426. doi:10.5114/aoms.2015.50974

9. Lindholm P, Lundgren CE. The physiology and pathophysiology of human breath-hold diving. J Appl Physiol (1985). 2009;106(1):284-292. doi:10.1152/japplphysiol.90991.2008

10. Tansey EA, Johnson CD. Recent advances in thermoregulation. Adv Physiol Educ. 2015;39(3):139-148. doi:10.1152/advan.00126.2014

11. Alboni P, Alboni M. Vasovagal syncope as a manifestation of an evolutionary selected trait. J Atr Fibrillation. 2014;7(2):1035. doi:10.4022/jafib.1035

12. Badran BW, Austelle CW. The future is noninvasive: a brief review of the evolution and clinical utility of vagus nerve stimulation. Focus (Am Psychiatr Publ). 2022;20(1):3-7. doi:10.1176/appi.focus.20210023

13. Suarez-Roca H, Mamoun N, Sigurdson MI, et al. Baroreceptor modulation of the cardiovascular system, pain, consciousness, and cognition. Compr Physiol. 2021;11(2):1373-1423. doi:10.1002/cphy.c190038

14. Pinna T, Edwards DJ. A systematic review of associations between interoception, vagal tone, and emotional regulation: potential applications for mental health, wellbeing, psychological flexibility, and chronic conditions. Front Psychol. 2020;11:1792. doi:10.3389/fpsyg.2020.01792

15. Howland RH. Vagus nerve stimulation. Curr Behav Neurosci Rep. 2014 Jun;1(2):64-73. doi:10.1007/s40473-014-0010-5

16. Panneton WM, Gan Q. The mammalian diving response: inroads to its neural control. Front Neurosci. 2020;14:524. doi:10.3389/fnins.2020.00524

17. Khurana RK, Wu R. The cold face test: a non-baroreflex mediated test of cardiac vagal function. Clin Auton Res. 2006;16(3):202-207. doi:10.1007/s10286-006-0332-9

18. Montirosso R, Provenzi L, Tronick E, et al. Vagal tone as a biomarker of long-term memory for a stressful social event at 4 months. Dev Psychobiol. 2014;56(7):1564-1574. doi:10.1002/dev.21251

19. Hansen AL, Johnsen BH, Thayer JF. Vagal influence on working memory and attention. Int J Psychophysiol. 2003;48(3):263-274. doi:10.1016/s0167-8760(03)00073-4

20. Lewis SL. Aetiology of transient global amnesia. Lancet. 1998;352(9125):397-399. doi:10.1016/S0140-6736(98)01442-1

21. Han K, Chao AC, Chang FC, et al. Obstruction of venous drainage linked to transient global amnesia. PLoS One. 2015;10(7):e0132893. doi:10.1371/journal.pone.0132893

22. Picciotto MR, Higley MJ, Mineur YS. Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron. 2012;76(1):116-129. doi:10.1016/j.neuron.2012.08.036

23. Dulawa SC, Janowsky DS. Cholinergic regulation of mood: from basic and clinical studies to emerging therapeutics. Mol Psychiatry. 2019;24(5):694-709. doi:10.1038/s41380-018-0219-x

24. Grande LA, Loeser JD, Samii A. Recurrent transient global amnesia with intrathecal baclofen. Anesth Analg. 2008;106(4):1284-1287. doi:10.1213/ane.0b013e318165e1c6

25. Carrard J, Lambert AC, Genné D. Transient global amnesia following a whole-body cryotherapy session. BMJ Case Rep. 2017;2017:bcr2017221431. doi:10.1136/bcr-2017-221431

26. Jeong M, Kim WS, Kim AR, et al. Medical procedure-related transient global amnesia. Eur Neurol. 2018;80(1-2):42-49. doi:10.1159/000493163

27. Shah B, Hussain MW. Concussion causing transient global amnesia: further insights into pathophysiology? Neurology. 2020;95(20 Suppl 1):S16. doi:10.1212/01.wnl.0000720020.86134.9d

More on an asymmetric life

I enjoy receiving Current Psychiatry each month and read Dr. Nasrallah's editorials with great interest, as there is often an interesting angle to the topic. However, I found your recent editorial (“The joys and rewards of an asymmetric life,” Current Psychiatry, May 2023, p. 7-8,16, doi:10.12788/cp.0361) perplexing. You and I (and most male physicians) have certainly been privileged, but not everyone gets to lead an asymmetric life. For many of our patients, an unbalanced life is part and parcel of their mental illness.

Too often, families bear the burden of an individual’s hyperfocused pursuits. I hope your wife has been able to pursue her occupation with the same zeal and commitment. We have all read biographies of driven individuals and, unfortunately, someone pays the price for another’s success. For every Steve Jobs, there is a Lisa Jobs.

If we were surgeons, I would applaud your essay. However, we are psychiatrists. If anything, we balance out the reductionist forces in medicine. When every other physician claims a cure with medications or procedures, we look at all aspects of the patient’s life to find the appropriate treatment. At least that’s what we should be doing.

I was part of the first class of residents to work under the 80-hours-per-week restrictions. I was grateful for the extra time to rest, exercise, and spend time with my wife. The 80-hour restrictions improved resident wellness and had no impact on patient care. There are intangible benefits of diverting the mind from a chosen pursuit (such as creativity).

There is no doubt that becoming number 1 in any field requires a tremendous amount of determination, sacrifice, and effort. But not everyone gets to be first. Our society’s single-minded focus on being the best has had a major impact on mental health, especially for children. I hope you can address that in a future editorial.

Sudhir Nagaraja, DO, MS
Fredericksburg, Virginia

Dr. Nasrallah responds

Thank you for your letter about my editorial. You obviously believe in leading a balanced life, and that’s fine if you so choose. I described why I decided at an early age to lead an intensive, “purpose-driven life,” which requires investing much more time than others do, to achieve my lofty goals and excel in my area of expertise (academic psychiatry). It is really a “calling,” and those who score an extraordinary achievement (a moonshot) in their life, including Olympic gold medalists, entrepreneurs, inventors, or Nobel laureates, must do exactly what I do. I am not urging anyone to do what I have chosen to do in my life. Everyone defines for themselves what constitutes the pursuit of happiness.

You mentioned my wife. Let me assert that she is highly successful as a mother and as a research psychologist. She is my extremely valuable life partner and very supportive of what I do. I am fortunate to have chosen well!

Continue to: More on transient global amnesia

Your recent article on transient global amnesia (TGA) (“Transient global amnesia: Psychiatric precipitants, features, and comorbidities,” Current Psychiatry, April 2023, p. 30-35,40, doi:10.12788/cp.0345) is an encouragement for psychiatrists to bring their skills to explore disorders often seen as the primary task of neurology. The article presents a woman with a history of trauma who received a severe emotional shock that triggered TGA. The discussion of a proposed treatment (lorazepam) brings a psychopharmacologic focus to TGA.

I witnessed TGA, experienced by my brother, while on a surf trip. After bodyboarding for about an hour in cold water, wearing a full wet suit and hood, he met me on the beach. He recognized me and knew my name but had no idea where we were, how we got there, or other events from earlier that morning. There was no stressor, just the usual surfing excitement. We went to a local emergency department, where the physical examination, usual laboratory tests, and neuroimaging were normal. After approximately 5 hours, he began to fully recall recent events. Ten years later, there has been no recurrence. The only change in his surfing habits has been to avoid using a hood with neck coverage.

In 2022, Papadis et al¹ described a case of concurrent Takotsubo cardio­myopathy and TGA, noting that cardiovascular dysfunction and neuro­logic dysfunction may be provoked by an emotional or stressful situation. The interesting observations of capture myopathy from animal literature appear similar to human reactions to trauma.^1-3

Case reports of scopolamine intoxication have been linked to TGA. Severe memory disturbances, characteristics of dry mouth, blurred vision, and tachycardia were evident. Certain South American plant extracts popularly known as “Burundanga” have anticholinergic effects. Severe anterograde amnesia and submissiveness represent the 2 most notorious clinical signs of Burundanga intoxication.⁴

As one reviews single and groups of case studies, several things stand out. The hallmark of TGA is the sudden inability to make new memories, which resolves in a few hours. The brief and isolated dysfunction is what distinguishes this condition from most episodic disorders, but a clinician should not prognosticate too much without screening for ischemic or metabolic disturbance. Common associated precursors include Valsalva-associated activities, emotional stress with anxiety, acute pain, cold water immersion, static neck posture, and age older than 55.^5,6 

Neuropsychiatric disorders involve the neuron and its connections. Major reflexes automate the processes of the “neurocardiac” axis. The vasovagal reflex (Barcroft/Edholm reflex), diving reflex, baroreceptor reflex, Cushing reflex, and others depend upon the conversion of a mechanical stimulus to neurotransmission. The reflexes have sensors, afferent paths, a central processing, and efferent paths that lead to events or experiences. CNS processing is complex but the brainstem, amygdala, prefrontal cortex, and some cortical regions are involved. Neurocardiac reactions can come from pathologic events, including ischemia, metabolic disturbance, pain signals, or emotional effects within the axis.^7-11

Understanding neurocardiac reflexes may help our progress with challenging clinical conditions, such as chronic pain, trauma, and cognitive impairment. The broad use of vagus nerve stimulation is one indicator of the power of this focus.^12-19 Lewis²⁰ suggested increased susceptibility to retrograde jugular venous flow could cause regional brain ischemia, resulting in TGA. The competency of jugular venous valves during the Valsalva maneuver could be assessed with Doppler ultrasound. Abnormalities could be managed, and results assessed.^20,21 Vascular shunting from memory regions in the brain to essential neurocardiac control areas should be considered.

Cholinergic processes are active in the parasympathetic nervous system, sustained attention, working memory, executive functions, and mood. Increased central cholinergic activity may lead to depression. Scopolamine, in its therapeutic range, has antidepressant effects but in toxic doses is a dissociative agent.^22,23 While cholinesterase inhibitors are used in Alzheimer disease, cholinergic agonists have yet to play a large role in general psychiatry or functional neurology.

TGA continues to provide a window into memory, functional disorders, psychological defenses, and adaptive neurocardiac processes. Continued clinical care and research might include gradual adaptation to cold water immersion, caution with the Valsalva maneuver, cholinergic support, managing the trapped response, avoiding interference with normal jugular flow, and evaluation for jugular venous insufficiency.

Because a variety of medical procedures can trigger TGA, health care professionals in many fields need to understand this symptom complex.^24-27 Thanks to the authors for raising the awareness of TGA for psychiatrists.

Mark Chandler, MD
Durham, North Carolina

References

1. Papadis A, Svab S, Brugger N, et al. “Broken heart” and “broken brain”: which connection? Cardiol Res. 2022;13(1):65-70. doi:10.14740/cr1336

2. Blumstein DT, Buckner J, Shah S, et al. The evolution of capture myopathy in hooved mammals: a model for human stress cardiomyopathy? Evol Med Public Health. 2015;2015(1):195-203. doi:10.1093/emph/eov015

3. Seguel M, Paredes E, Pavés H, et al. Capture-induced stress cardiomyopathy in South American fur seal pups (Arctophoca australis gracilis). Marine Mammal Science. 2014;30(3): 1149-1157. https://doi.org/10.1111/mms.12079

4. Ardila A, Moreno C. Scopolamine intoxication as a model of transient global amnesia. Brain Cogn. 1991;15(2):236-245. doi:10.1016/0278-2626(91)90028-7

5. Bartsch T, Deuschl G. Transient global amnesia: functional anatomy and clinical implications. Lancet Neurol. 2010;9(2):205-214. doi:10.1016/S1474-4422(09)70344-8

6. Spiegel DR, Smith J, Wade RR, et al. Transient global amnesia: current perspectives. Neuropsychiatr Dis Treat. 2017;13:2691-2703. doi:10.2147/NDT.S130710

7. Yartsev A. Cardiac reflexes. August 15, 2020. Updated May 19, 2023. Accessed June 12, 2023. https://derangedphysiology.com/main/cicm-primary-exam/required-reading/cardiovascular-system/Chapter%20491/cardiac-reflexes

8. Lemaitre F, Chowdhury T, Schaller B. The trigeminocardiac reflex - a comparison with the diving reflex in humans. Arch Med Sci. 2015;11(2):419-426. doi:10.5114/aoms.2015.50974

9. Lindholm P, Lundgren CE. The physiology and pathophysiology of human breath-hold diving. J Appl Physiol (1985). 2009;106(1):284-292. doi:10.1152/japplphysiol.90991.2008

10. Tansey EA, Johnson CD. Recent advances in thermoregulation. Adv Physiol Educ. 2015;39(3):139-148. doi:10.1152/advan.00126.2014

11. Alboni P, Alboni M. Vasovagal syncope as a manifestation of an evolutionary selected trait. J Atr Fibrillation. 2014;7(2):1035. doi:10.4022/jafib.1035

12. Badran BW, Austelle CW. The future is noninvasive: a brief review of the evolution and clinical utility of vagus nerve stimulation. Focus (Am Psychiatr Publ). 2022;20(1):3-7. doi:10.1176/appi.focus.20210023

13. Suarez-Roca H, Mamoun N, Sigurdson MI, et al. Baroreceptor modulation of the cardiovascular system, pain, consciousness, and cognition. Compr Physiol. 2021;11(2):1373-1423. doi:10.1002/cphy.c190038

14. Pinna T, Edwards DJ. A systematic review of associations between interoception, vagal tone, and emotional regulation: potential applications for mental health, wellbeing, psychological flexibility, and chronic conditions. Front Psychol. 2020;11:1792. doi:10.3389/fpsyg.2020.01792

15. Howland RH. Vagus nerve stimulation. Curr Behav Neurosci Rep. 2014 Jun;1(2):64-73. doi:10.1007/s40473-014-0010-5

16. Panneton WM, Gan Q. The mammalian diving response: inroads to its neural control. Front Neurosci. 2020;14:524. doi:10.3389/fnins.2020.00524

17. Khurana RK, Wu R. The cold face test: a non-baroreflex mediated test of cardiac vagal function. Clin Auton Res. 2006;16(3):202-207. doi:10.1007/s10286-006-0332-9

18. Montirosso R, Provenzi L, Tronick E, et al. Vagal tone as a biomarker of long-term memory for a stressful social event at 4 months. Dev Psychobiol. 2014;56(7):1564-1574. doi:10.1002/dev.21251

19. Hansen AL, Johnsen BH, Thayer JF. Vagal influence on working memory and attention. Int J Psychophysiol. 2003;48(3):263-274. doi:10.1016/s0167-8760(03)00073-4

20. Lewis SL. Aetiology of transient global amnesia. Lancet. 1998;352(9125):397-399. doi:10.1016/S0140-6736(98)01442-1

21. Han K, Chao AC, Chang FC, et al. Obstruction of venous drainage linked to transient global amnesia. PLoS One. 2015;10(7):e0132893. doi:10.1371/journal.pone.0132893

22. Picciotto MR, Higley MJ, Mineur YS. Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron. 2012;76(1):116-129. doi:10.1016/j.neuron.2012.08.036

23. Dulawa SC, Janowsky DS. Cholinergic regulation of mood: from basic and clinical studies to emerging therapeutics. Mol Psychiatry. 2019;24(5):694-709. doi:10.1038/s41380-018-0219-x

24. Grande LA, Loeser JD, Samii A. Recurrent transient global amnesia with intrathecal baclofen. Anesth Analg. 2008;106(4):1284-1287. doi:10.1213/ane.0b013e318165e1c6

25. Carrard J, Lambert AC, Genné D. Transient global amnesia following a whole-body cryotherapy session. BMJ Case Rep. 2017;2017:bcr2017221431. doi:10.1136/bcr-2017-221431

26. Jeong M, Kim WS, Kim AR, et al. Medical procedure-related transient global amnesia. Eur Neurol. 2018;80(1-2):42-49. doi:10.1159/000493163

27. Shah B, Hussain MW. Concussion causing transient global amnesia: further insights into pathophysiology? Neurology. 2020;95(20 Suppl 1):S16. doi:10.1212/01.wnl.0000720020.86134.9d

Multiple sclerosis (MS) is an immune-mediated demyelinating disorder. There are 2 broad categories of MS: relapsing, also called active MS; and progressive MS. Unfortunately, there is no cure for MS, but disease-modifying therapies (DMTs) can help prevent relapses and new central nervous system lesions in people living with active MS. For patients with the most common type of MS, relapsing-remitting MS (RRMS), DMTs are typically continued for decades while the patient has active disease. RRMS will usually transition to secondary progressive MS (SPMS), which can present as active SPMS or nonactive SPMS. The latter is the type of MS most people with RRMS eventually experience.

A 2019 study estimated that nearly 1 million people in the United States were living with MS.¹ This population estimate indicated the peak age-specific prevalence of MS was 55 to 64 years. Population data demonstrate improved mortality rates for people diagnosed with MS from 1997 to 2012 compared with prior years.² Therefore, the management of nonactive SPMS is an increasingly significant area of need. There are currently no DMTs on the market approved for nonactive SPMS, and lifelong DMTs in these patients are neither indicated nor supported by evidence. Nevertheless, the discontinuation of DMTs in nonactive SPMS has been a long-debated topic with varied opinions on how and when to discontinue.

The 2018 American Academy of Neurology (AAN) guideline recommends that clinicians advise patients with SPMS to discontinue DMT use if they do not have ongoing relapses (or gadolinium-enhanced lesions on magnetic resonance imaging activity) or have not been ambulatory (Expanded Disability Status Scale [EDSS] ≥ 7) for ≥ 2 years.³ In recent years, there has been increased research on nonactive SPMS, specifically on discontinuation of DMTs. This clinical review assesses the recent evidence from a variety of standpoints, including the effect of discontinuing DMTs on the MS disease course and quality of life (QOL) and the perspectives of patients living with MS. Based on this evidence, a conversation guide will be presented as a framework to aid with the clinician-patient discussion on discontinuing MS DMTs.

Disease Modifying Therapies

Roos and colleagues used data from 2 large MS cohorts: MSBase and Observatoire Français de la Sclérose en Plaques (OFSEP) to compare high-efficacy vs low-efficacy DMT in both active and nonactive SPMS.⁴ In the active SPMS group, the strength of DMTs did not change disability progression, but high-efficacy DMTs reduced relapses better than the low-efficacy DMTs. On the other hand, the nonactive SPMS group saw no difference between DMTs in both relapse risk and disability progression. Another observational study of 221 patients with RRMS who discontinued DMTs noted that there were 2 independent predictors for the absence of relapse following DMT discontinuation: being aged > 45 years and the lack of relapse for ≥ 4 years prior to DMT discontinuation.⁵ Though these patients still may have been classified as RRMS, both these independent predictors for stability postdiscontinuation of DMTs are the typical characteristics of a nonactive SPMS patient.

Pathophysiology may help explain why DMT discontinuation seems to produce no adverse clinical outcomes in people with nonactive SPMS. Nonactive SPMS, which follows after RRMS, is largely correlated with age. In nonactive SPMS, there is less B and T lymphocyte migration across the blood-brain barrier. Furthermore, a lifetime of low-grade inflammation during the RRMS phase results in axonal damage and declined repair capacity, which produces the predominance of neurodegeneration in the nonactive SPMS disease process.⁶ This pathophysiologic difference between active and nonactive disease not only explains the different symptomatology of these MS subtypes, but also could explain why drugs that target the inflammatory processes more characteristic of active disease are not effective in nonactive SPMS.

Other recent studies explored the impact of age on DMT efficacy for patients with nonactive SPMS. A meta-analysis by Weidman and colleagues pooled trial data across multiple DMT classes in > 28,000 patients.⁷ The resulting regression model predicted zero efficacy of any DMT in patients who are aged > 53 years. High-efficacy DMTs only outperformed low-efficacy DMTs in people aged < 40.5 years. Another observational study by Hua and colleagues saw a similar result.⁸ This study included patients who discontinued DMT who were aged ≥ 60 years. The median follow-up time was 5.3 years. Of the 178 patients who discontinued DMTs, only 1 patient had a relapse. In this study, the age for participation provided a higher likelihood that patients included were in nonactive SPMS. Furthermore, the outcome reflects the typical presentation of nonactive SPMS where, despite the continuation or discontinuation of DMT, there was a lack of relapses. When comparing patients who discontinued DMTs with those who continued use, there was no significant difference in their 25-foot walk times, which is an objective marker for a more progressive symptom seen in nonactive MS.

The DISCOMS trial (NCT03073603) has been completed, but full results are not yet published. In this noninferiority trial, > 250 patients aged ≥ 55 years were assessed on a variety of outcomes, including relapses, EDSS score, and QOL. MS subtypes were considered at baseline, and subgroup analysis looking particularly at the SPMS population could provide further insight into its effect on MS course.

Quality of Life

Whether discontinuation of DMTs is worth considering in nonactive SPMS, it is also important to consider the risks and burdens associated with continuation. Medication administration burdens come with all MS DMTs whether there is the need to inject oneself, increased pill burden, or travel to an infusion clinic. The ever-rising costs of DMTs also can be a financial burden to the patient.⁹ All MS DMTs carry risks of adverse effects (AEs). These can range from a mild injection site reaction to severe infection, depending on the DMT used. Many of these severe AEs, such as opportunistic infections and cancer, have been associated with either an increased risk of occurrence and/or worsened outcomes in older adults who remain on DMTs, particularly moderate- to high-efficacy DMTs, such as sphingosine-1- phosphate receptor modulators, fumarates, natalizumab, alemtuzumab, cladribine, and anti-CD20 antibodies.¹⁰ In a 2019 survey of 377 patients with MS, 63.8% of respondents ranked safety as the most important reason they would consider discontinuing their DMTs.¹¹ In addition, a real-world study comparing people with nonactive SPMS who continued DMTs vs those who discontinued found that discontinuers reported better QOL.⁸

Conversation Guide for Discontinuing Therapies

The 2019 survey that assessed reasons for discontinuation also asked people with nonactive SPMS whether they thought they were in a nonactive disease stage, and what was their likelihood they would stop DMTs.¹¹ Interestingly, only 59.4% of respondents self-assessed their MS as nonactive, and just 11.9% of respondents were willing to discontinue DMTs.¹¹ These results suggest that there may be a need for patient education about nonactive SPMS and the rationale to continue or discontinue DMTs. Thus, before broaching the topic of discontinuation, explaining the nonactive SPMS subtype is important.

Even with a good understanding of nonactive SPMS, patients may be hesitant to stop using DMTs that they previously relied on to keep their MS stable. The 2019 survey ranked physician recommendation as the third highest reason to discontinue DMTs.¹¹ Taking the time to explain the clinical evidence for DMT discontinuation may help patients better understand a clinician’s recommendation and inspire more confidence.

Another important aspect of DMT discontinuation decision making is creating a plan for how the patient will be monitored to provide assurance if they experience a relapse. The 2019 survey asked patients what would be most important to them for their management plan after discontinuing DMT; magnetic resonance imaging and neurologic examination monitoring ranked the highest.¹¹ The plan should include timing for follow-up appointments and imaging, providing the patient comfort in knowing their MS will be monitored and verified for the relapse stability that is expected from nonactive SPMS. In the rare case a relapse does occur, having a contingency plan and noting the possibility of restarting DMTs is an integral part of reassuring the patient that their decision to discontinue DMTs will be treated with the utmost caution and individualized to their needs.

Lastly, highlighting which aspects of MS treatment will continue to be a priority in nonactive SPMS, such as symptomatic medication management and nonpharmacologic therapy, is important for the patient to recognize that there are still opportunities to manage this phase of MS. There are many lifestyle modifications that can be considered complementary to medical management of MS at any stage of the disease. Vascular comorbidities, such as hypertension, hyperlipidemia, and diabetes, have been associated with more rapid disability progression in MS.¹² Optimized management of these diseases may slow disability progression, in addition to the benefit of improved outcomes of the vascular comorbidity. Various formats of exercise have been studied in the MS population. A meta-analysis of aerobic, resistance, and combined exercise found benefits in these formats on health-related QOL.¹³

Many dietary strategies have been studied in MS. A recent network meta-analysis reviewed some of the more commonly studied diets, including low-fat, modified Mediterranean, ketogenic, anti-inflammatory, Paleolithic, intermittent fasting, and calorie restriction vs a usual diet.¹⁴ Although the overall quality of evidence was low, the Paleolithic and modified Mediterranean showed greater reductions in fatigue, as well as increased physical and mental QOL compared with a usual diet. The low-fat diet was associated with a reduction in fatigue. Many of these lifestyle modifications may complement optimized vascular comorbidity treatment; however, any exercise regimen or dietary change should be considered with the whole health of the patient in mind.

As with any health care decision, it is important to involve the patient in a joint decision regarding their care. This may mean giving the patient time to think about the information presented, do their own research, talk to family members or other clinicians, etc. The decision to discontinue DMT may not happen at the same appointment it is initially brought up at. It may even be reasonable to revisit the conversation later if discontinuation is not something the patient is amenable to at the time.

Conclusions

There is high-quality evidence that discontinuing DMTs in nonactive SPMS is not a major detriment to the MS disease course. Current literature also suggests that there may be benefits to discontinuation in this MS subtype in terms of QOL and meeting patient values. Additional research particularly in the nonactive SPMS population will continue to improve the knowledge and awareness of this aspect of MS DMT management. The growing evidence in this area may make discontinuation of DMT in nonactive SPMS a less-debatable topic, but it is still a major treatment decision that clinicians must thoroughly discuss with the patient to provide high-quality, patient-centered care.

Multiple sclerosis (MS) is an immune-mediated demyelinating disorder. There are 2 broad categories of MS: relapsing, also called active MS; and progressive MS. Unfortunately, there is no cure for MS, but disease-modifying therapies (DMTs) can help prevent relapses and new central nervous system lesions in people living with active MS. For patients with the most common type of MS, relapsing-remitting MS (RRMS), DMTs are typically continued for decades while the patient has active disease. RRMS will usually transition to secondary progressive MS (SPMS), which can present as active SPMS or nonactive SPMS. The latter is the type of MS most people with RRMS eventually experience.

A 2019 study estimated that nearly 1 million people in the United States were living with MS.¹ This population estimate indicated the peak age-specific prevalence of MS was 55 to 64 years. Population data demonstrate improved mortality rates for people diagnosed with MS from 1997 to 2012 compared with prior years.² Therefore, the management of nonactive SPMS is an increasingly significant area of need. There are currently no DMTs on the market approved for nonactive SPMS, and lifelong DMTs in these patients are neither indicated nor supported by evidence. Nevertheless, the discontinuation of DMTs in nonactive SPMS has been a long-debated topic with varied opinions on how and when to discontinue.

The 2018 American Academy of Neurology (AAN) guideline recommends that clinicians advise patients with SPMS to discontinue DMT use if they do not have ongoing relapses (or gadolinium-enhanced lesions on magnetic resonance imaging activity) or have not been ambulatory (Expanded Disability Status Scale [EDSS] ≥ 7) for ≥ 2 years.³ In recent years, there has been increased research on nonactive SPMS, specifically on discontinuation of DMTs. This clinical review assesses the recent evidence from a variety of standpoints, including the effect of discontinuing DMTs on the MS disease course and quality of life (QOL) and the perspectives of patients living with MS. Based on this evidence, a conversation guide will be presented as a framework to aid with the clinician-patient discussion on discontinuing MS DMTs.

Disease Modifying Therapies

Roos and colleagues used data from 2 large MS cohorts: MSBase and Observatoire Français de la Sclérose en Plaques (OFSEP) to compare high-efficacy vs low-efficacy DMT in both active and nonactive SPMS.⁴ In the active SPMS group, the strength of DMTs did not change disability progression, but high-efficacy DMTs reduced relapses better than the low-efficacy DMTs. On the other hand, the nonactive SPMS group saw no difference between DMTs in both relapse risk and disability progression. Another observational study of 221 patients with RRMS who discontinued DMTs noted that there were 2 independent predictors for the absence of relapse following DMT discontinuation: being aged > 45 years and the lack of relapse for ≥ 4 years prior to DMT discontinuation.⁵ Though these patients still may have been classified as RRMS, both these independent predictors for stability postdiscontinuation of DMTs are the typical characteristics of a nonactive SPMS patient.

Pathophysiology may help explain why DMT discontinuation seems to produce no adverse clinical outcomes in people with nonactive SPMS. Nonactive SPMS, which follows after RRMS, is largely correlated with age. In nonactive SPMS, there is less B and T lymphocyte migration across the blood-brain barrier. Furthermore, a lifetime of low-grade inflammation during the RRMS phase results in axonal damage and declined repair capacity, which produces the predominance of neurodegeneration in the nonactive SPMS disease process.⁶ This pathophysiologic difference between active and nonactive disease not only explains the different symptomatology of these MS subtypes, but also could explain why drugs that target the inflammatory processes more characteristic of active disease are not effective in nonactive SPMS.

Other recent studies explored the impact of age on DMT efficacy for patients with nonactive SPMS. A meta-analysis by Weidman and colleagues pooled trial data across multiple DMT classes in > 28,000 patients.⁷ The resulting regression model predicted zero efficacy of any DMT in patients who are aged > 53 years. High-efficacy DMTs only outperformed low-efficacy DMTs in people aged < 40.5 years. Another observational study by Hua and colleagues saw a similar result.⁸ This study included patients who discontinued DMT who were aged ≥ 60 years. The median follow-up time was 5.3 years. Of the 178 patients who discontinued DMTs, only 1 patient had a relapse. In this study, the age for participation provided a higher likelihood that patients included were in nonactive SPMS. Furthermore, the outcome reflects the typical presentation of nonactive SPMS where, despite the continuation or discontinuation of DMT, there was a lack of relapses. When comparing patients who discontinued DMTs with those who continued use, there was no significant difference in their 25-foot walk times, which is an objective marker for a more progressive symptom seen in nonactive MS.

The DISCOMS trial (NCT03073603) has been completed, but full results are not yet published. In this noninferiority trial, > 250 patients aged ≥ 55 years were assessed on a variety of outcomes, including relapses, EDSS score, and QOL. MS subtypes were considered at baseline, and subgroup analysis looking particularly at the SPMS population could provide further insight into its effect on MS course.

Quality of Life

Whether discontinuation of DMTs is worth considering in nonactive SPMS, it is also important to consider the risks and burdens associated with continuation. Medication administration burdens come with all MS DMTs whether there is the need to inject oneself, increased pill burden, or travel to an infusion clinic. The ever-rising costs of DMTs also can be a financial burden to the patient.⁹ All MS DMTs carry risks of adverse effects (AEs). These can range from a mild injection site reaction to severe infection, depending on the DMT used. Many of these severe AEs, such as opportunistic infections and cancer, have been associated with either an increased risk of occurrence and/or worsened outcomes in older adults who remain on DMTs, particularly moderate- to high-efficacy DMTs, such as sphingosine-1- phosphate receptor modulators, fumarates, natalizumab, alemtuzumab, cladribine, and anti-CD20 antibodies.¹⁰ In a 2019 survey of 377 patients with MS, 63.8% of respondents ranked safety as the most important reason they would consider discontinuing their DMTs.¹¹ In addition, a real-world study comparing people with nonactive SPMS who continued DMTs vs those who discontinued found that discontinuers reported better QOL.⁸

Conversation Guide for Discontinuing Therapies

The 2019 survey that assessed reasons for discontinuation also asked people with nonactive SPMS whether they thought they were in a nonactive disease stage, and what was their likelihood they would stop DMTs.¹¹ Interestingly, only 59.4% of respondents self-assessed their MS as nonactive, and just 11.9% of respondents were willing to discontinue DMTs.¹¹ These results suggest that there may be a need for patient education about nonactive SPMS and the rationale to continue or discontinue DMTs. Thus, before broaching the topic of discontinuation, explaining the nonactive SPMS subtype is important.

Even with a good understanding of nonactive SPMS, patients may be hesitant to stop using DMTs that they previously relied on to keep their MS stable. The 2019 survey ranked physician recommendation as the third highest reason to discontinue DMTs.¹¹ Taking the time to explain the clinical evidence for DMT discontinuation may help patients better understand a clinician’s recommendation and inspire more confidence.

Another important aspect of DMT discontinuation decision making is creating a plan for how the patient will be monitored to provide assurance if they experience a relapse. The 2019 survey asked patients what would be most important to them for their management plan after discontinuing DMT; magnetic resonance imaging and neurologic examination monitoring ranked the highest.¹¹ The plan should include timing for follow-up appointments and imaging, providing the patient comfort in knowing their MS will be monitored and verified for the relapse stability that is expected from nonactive SPMS. In the rare case a relapse does occur, having a contingency plan and noting the possibility of restarting DMTs is an integral part of reassuring the patient that their decision to discontinue DMTs will be treated with the utmost caution and individualized to their needs.

Lastly, highlighting which aspects of MS treatment will continue to be a priority in nonactive SPMS, such as symptomatic medication management and nonpharmacologic therapy, is important for the patient to recognize that there are still opportunities to manage this phase of MS. There are many lifestyle modifications that can be considered complementary to medical management of MS at any stage of the disease. Vascular comorbidities, such as hypertension, hyperlipidemia, and diabetes, have been associated with more rapid disability progression in MS.¹² Optimized management of these diseases may slow disability progression, in addition to the benefit of improved outcomes of the vascular comorbidity. Various formats of exercise have been studied in the MS population. A meta-analysis of aerobic, resistance, and combined exercise found benefits in these formats on health-related QOL.¹³

Many dietary strategies have been studied in MS. A recent network meta-analysis reviewed some of the more commonly studied diets, including low-fat, modified Mediterranean, ketogenic, anti-inflammatory, Paleolithic, intermittent fasting, and calorie restriction vs a usual diet.¹⁴ Although the overall quality of evidence was low, the Paleolithic and modified Mediterranean showed greater reductions in fatigue, as well as increased physical and mental QOL compared with a usual diet. The low-fat diet was associated with a reduction in fatigue. Many of these lifestyle modifications may complement optimized vascular comorbidity treatment; however, any exercise regimen or dietary change should be considered with the whole health of the patient in mind.

As with any health care decision, it is important to involve the patient in a joint decision regarding their care. This may mean giving the patient time to think about the information presented, do their own research, talk to family members or other clinicians, etc. The decision to discontinue DMT may not happen at the same appointment it is initially brought up at. It may even be reasonable to revisit the conversation later if discontinuation is not something the patient is amenable to at the time.

Conclusions

There is high-quality evidence that discontinuing DMTs in nonactive SPMS is not a major detriment to the MS disease course. Current literature also suggests that there may be benefits to discontinuation in this MS subtype in terms of QOL and meeting patient values. Additional research particularly in the nonactive SPMS population will continue to improve the knowledge and awareness of this aspect of MS DMT management. The growing evidence in this area may make discontinuation of DMT in nonactive SPMS a less-debatable topic, but it is still a major treatment decision that clinicians must thoroughly discuss with the patient to provide high-quality, patient-centered care.

Multiple sclerosis (MS) is an immune-mediated demyelinating disorder. There are 2 broad categories of MS: relapsing, also called active MS; and progressive MS. Unfortunately, there is no cure for MS, but disease-modifying therapies (DMTs) can help prevent relapses and new central nervous system lesions in people living with active MS. For patients with the most common type of MS, relapsing-remitting MS (RRMS), DMTs are typically continued for decades while the patient has active disease. RRMS will usually transition to secondary progressive MS (SPMS), which can present as active SPMS or nonactive SPMS. The latter is the type of MS most people with RRMS eventually experience.

A 2019 study estimated that nearly 1 million people in the United States were living with MS.¹ This population estimate indicated the peak age-specific prevalence of MS was 55 to 64 years. Population data demonstrate improved mortality rates for people diagnosed with MS from 1997 to 2012 compared with prior years.² Therefore, the management of nonactive SPMS is an increasingly significant area of need. There are currently no DMTs on the market approved for nonactive SPMS, and lifelong DMTs in these patients are neither indicated nor supported by evidence. Nevertheless, the discontinuation of DMTs in nonactive SPMS has been a long-debated topic with varied opinions on how and when to discontinue.

The 2018 American Academy of Neurology (AAN) guideline recommends that clinicians advise patients with SPMS to discontinue DMT use if they do not have ongoing relapses (or gadolinium-enhanced lesions on magnetic resonance imaging activity) or have not been ambulatory (Expanded Disability Status Scale [EDSS] ≥ 7) for ≥ 2 years.³ In recent years, there has been increased research on nonactive SPMS, specifically on discontinuation of DMTs. This clinical review assesses the recent evidence from a variety of standpoints, including the effect of discontinuing DMTs on the MS disease course and quality of life (QOL) and the perspectives of patients living with MS. Based on this evidence, a conversation guide will be presented as a framework to aid with the clinician-patient discussion on discontinuing MS DMTs.

Disease Modifying Therapies

Roos and colleagues used data from 2 large MS cohorts: MSBase and Observatoire Français de la Sclérose en Plaques (OFSEP) to compare high-efficacy vs low-efficacy DMT in both active and nonactive SPMS.⁴ In the active SPMS group, the strength of DMTs did not change disability progression, but high-efficacy DMTs reduced relapses better than the low-efficacy DMTs. On the other hand, the nonactive SPMS group saw no difference between DMTs in both relapse risk and disability progression. Another observational study of 221 patients with RRMS who discontinued DMTs noted that there were 2 independent predictors for the absence of relapse following DMT discontinuation: being aged > 45 years and the lack of relapse for ≥ 4 years prior to DMT discontinuation.⁵ Though these patients still may have been classified as RRMS, both these independent predictors for stability postdiscontinuation of DMTs are the typical characteristics of a nonactive SPMS patient.

Pathophysiology may help explain why DMT discontinuation seems to produce no adverse clinical outcomes in people with nonactive SPMS. Nonactive SPMS, which follows after RRMS, is largely correlated with age. In nonactive SPMS, there is less B and T lymphocyte migration across the blood-brain barrier. Furthermore, a lifetime of low-grade inflammation during the RRMS phase results in axonal damage and declined repair capacity, which produces the predominance of neurodegeneration in the nonactive SPMS disease process.⁶ This pathophysiologic difference between active and nonactive disease not only explains the different symptomatology of these MS subtypes, but also could explain why drugs that target the inflammatory processes more characteristic of active disease are not effective in nonactive SPMS.

Other recent studies explored the impact of age on DMT efficacy for patients with nonactive SPMS. A meta-analysis by Weidman and colleagues pooled trial data across multiple DMT classes in > 28,000 patients.⁷ The resulting regression model predicted zero efficacy of any DMT in patients who are aged > 53 years. High-efficacy DMTs only outperformed low-efficacy DMTs in people aged < 40.5 years. Another observational study by Hua and colleagues saw a similar result.⁸ This study included patients who discontinued DMT who were aged ≥ 60 years. The median follow-up time was 5.3 years. Of the 178 patients who discontinued DMTs, only 1 patient had a relapse. In this study, the age for participation provided a higher likelihood that patients included were in nonactive SPMS. Furthermore, the outcome reflects the typical presentation of nonactive SPMS where, despite the continuation or discontinuation of DMT, there was a lack of relapses. When comparing patients who discontinued DMTs with those who continued use, there was no significant difference in their 25-foot walk times, which is an objective marker for a more progressive symptom seen in nonactive MS.

The DISCOMS trial (NCT03073603) has been completed, but full results are not yet published. In this noninferiority trial, > 250 patients aged ≥ 55 years were assessed on a variety of outcomes, including relapses, EDSS score, and QOL. MS subtypes were considered at baseline, and subgroup analysis looking particularly at the SPMS population could provide further insight into its effect on MS course.

Quality of Life

Whether discontinuation of DMTs is worth considering in nonactive SPMS, it is also important to consider the risks and burdens associated with continuation. Medication administration burdens come with all MS DMTs whether there is the need to inject oneself, increased pill burden, or travel to an infusion clinic. The ever-rising costs of DMTs also can be a financial burden to the patient.⁹ All MS DMTs carry risks of adverse effects (AEs). These can range from a mild injection site reaction to severe infection, depending on the DMT used. Many of these severe AEs, such as opportunistic infections and cancer, have been associated with either an increased risk of occurrence and/or worsened outcomes in older adults who remain on DMTs, particularly moderate- to high-efficacy DMTs, such as sphingosine-1- phosphate receptor modulators, fumarates, natalizumab, alemtuzumab, cladribine, and anti-CD20 antibodies.¹⁰ In a 2019 survey of 377 patients with MS, 63.8% of respondents ranked safety as the most important reason they would consider discontinuing their DMTs.¹¹ In addition, a real-world study comparing people with nonactive SPMS who continued DMTs vs those who discontinued found that discontinuers reported better QOL.⁸

Conversation Guide for Discontinuing Therapies

The 2019 survey that assessed reasons for discontinuation also asked people with nonactive SPMS whether they thought they were in a nonactive disease stage, and what was their likelihood they would stop DMTs.¹¹ Interestingly, only 59.4% of respondents self-assessed their MS as nonactive, and just 11.9% of respondents were willing to discontinue DMTs.¹¹ These results suggest that there may be a need for patient education about nonactive SPMS and the rationale to continue or discontinue DMTs. Thus, before broaching the topic of discontinuation, explaining the nonactive SPMS subtype is important.

Even with a good understanding of nonactive SPMS, patients may be hesitant to stop using DMTs that they previously relied on to keep their MS stable. The 2019 survey ranked physician recommendation as the third highest reason to discontinue DMTs.¹¹ Taking the time to explain the clinical evidence for DMT discontinuation may help patients better understand a clinician’s recommendation and inspire more confidence.

Another important aspect of DMT discontinuation decision making is creating a plan for how the patient will be monitored to provide assurance if they experience a relapse. The 2019 survey asked patients what would be most important to them for their management plan after discontinuing DMT; magnetic resonance imaging and neurologic examination monitoring ranked the highest.¹¹ The plan should include timing for follow-up appointments and imaging, providing the patient comfort in knowing their MS will be monitored and verified for the relapse stability that is expected from nonactive SPMS. In the rare case a relapse does occur, having a contingency plan and noting the possibility of restarting DMTs is an integral part of reassuring the patient that their decision to discontinue DMTs will be treated with the utmost caution and individualized to their needs.

Lastly, highlighting which aspects of MS treatment will continue to be a priority in nonactive SPMS, such as symptomatic medication management and nonpharmacologic therapy, is important for the patient to recognize that there are still opportunities to manage this phase of MS. There are many lifestyle modifications that can be considered complementary to medical management of MS at any stage of the disease. Vascular comorbidities, such as hypertension, hyperlipidemia, and diabetes, have been associated with more rapid disability progression in MS.¹² Optimized management of these diseases may slow disability progression, in addition to the benefit of improved outcomes of the vascular comorbidity. Various formats of exercise have been studied in the MS population. A meta-analysis of aerobic, resistance, and combined exercise found benefits in these formats on health-related QOL.¹³

Many dietary strategies have been studied in MS. A recent network meta-analysis reviewed some of the more commonly studied diets, including low-fat, modified Mediterranean, ketogenic, anti-inflammatory, Paleolithic, intermittent fasting, and calorie restriction vs a usual diet.¹⁴ Although the overall quality of evidence was low, the Paleolithic and modified Mediterranean showed greater reductions in fatigue, as well as increased physical and mental QOL compared with a usual diet. The low-fat diet was associated with a reduction in fatigue. Many of these lifestyle modifications may complement optimized vascular comorbidity treatment; however, any exercise regimen or dietary change should be considered with the whole health of the patient in mind.

As with any health care decision, it is important to involve the patient in a joint decision regarding their care. This may mean giving the patient time to think about the information presented, do their own research, talk to family members or other clinicians, etc. The decision to discontinue DMT may not happen at the same appointment it is initially brought up at. It may even be reasonable to revisit the conversation later if discontinuation is not something the patient is amenable to at the time.

Conclusions

There is high-quality evidence that discontinuing DMTs in nonactive SPMS is not a major detriment to the MS disease course. Current literature also suggests that there may be benefits to discontinuation in this MS subtype in terms of QOL and meeting patient values. Additional research particularly in the nonactive SPMS population will continue to improve the knowledge and awareness of this aspect of MS DMT management. The growing evidence in this area may make discontinuation of DMT in nonactive SPMS a less-debatable topic, but it is still a major treatment decision that clinicians must thoroughly discuss with the patient to provide high-quality, patient-centered care.

A duodenocaval fistula (DCF) is seen when a connection exists between the duodenum and the inferior vena cava. It is a rare entity that is commonly missed and presents a diagnostic challenge due to its nonspecific presenting symptoms.^1,2 Patients commonly present with gastrointestinal (GI) bleeding or sepsis. Here we present a case of a 37-year-old man who presented to the hospital for a workup related to melena but went into cardiac arrest prior to an esophagogastroduodenoscopy. Unfortunately, on autopsy, the patient was found to have a DCF. We highlight the diagnostic challenge associated with DCF and how in this case the presentation was confused by a diagnosis of possible transfusion-related acute lung injury (TRALI). To the best of our knowledge, this is also the first description of a case of DCF associated with food embolism to the lungs causing respiratory failure.

Case Presentation

A 37-year-old man with a history significant for bulimia presented to the hospital with a 3-day history of melena and reports of dizziness. The patient did not report being on any prescribed medications but noted that he took 4 aspirin daily to “calm his nerves.” The rest of the patient’s history was unremarkable aside from a reported history of induced emesis 3 to 4 times per week for an extended period up until 2 weeks before admission.

On admission, his vital signs demonstrated tachycardia and orthostatic hypotension. Pertinent findings on physical examination were skin pallor, a normal lung examination, mild epigastric tenderness, and guaiac-positive stools. He was alert and oriented to person, place, and time with no focal deficits. His admission laboratory tests were notable for a hemoglobin (Hb) level of 4.6 g/dL (reference range, 14-17.9), a white blood cell count of 13.5 K/cm (reference range, 4.5-11), an international normalized ratio of 1.21, a blood urea nitrogen of 61 mg/dL (reference range, 10-20), and a creatinine of 2.3 mg/dL (reference range, 0.8-1.4). The patient was placed on 2 L of oxygen via nasal cannula for comfort rather than true hypoxia. A chest X-ray on admission was negative with no signs of infiltrate, edema, or widened mediastinum. An abdominal X-ray was significant for a dilated stomach consistent with bulimia with no abdominal free air or signs of obstruction. The case was discussed with the gastroenterology service who felt that the patient needed to be more hemodynamically stable before pursuing endoscopic evaluation.

He was admitted to the intensive care unit and give a transfusion of 4 units of fresh frozen plasma and 2 packed red blood cells (PRBCs) without any issues. During the infusion of a third PRBC, he developed chills, tachycardia, and hypertension with accompanying respiratory distress characterized by wheezing, decreased breath sounds bilaterally, and a decrease in oxygen saturation to 70% on 2 L supplemental oxygen. He responded to treatment with meperidine, methylprednisolone sodium succinate, albuterol nebulizer, and acetaminophen. A new chest X-ray was read as “development of pulmonary edema vs bilateral pneumonitis.” A transfusion reaction was reported to the blood bank and a diagnosis of TRALI was considered. That evening, he completed a dose of platelets and another PRBC without difficulty after he was premedicated with meperidine, methylprednisolone sodium succinate, and acetaminophen. During the night, the patient spiked a temperature of 40.3 °C that was successfully treated with a cooling blanket and acetaminophen.

The following morning the patient was found to be tachypneic and tachycardic with his face mask off. His symptoms were corrected by replacing his face mask. He claimed he felt anxious about getting more transfusions and that he had breathing problems like this at home in the recent past. The patient requested an aspirin to calm his nerves. Over the course of the day, his Hb level dropped from 6.6 g/dL to 5.9 g/dL, and 2 washed leukopoor PRBCs were ordered.

The first unit was infused uneventfully, but after 125 cc of the second unit, the patient developed respiratory distress, rigors, and hypotension to 70/58 mm Hg despite premedication. He again was treated successfully with increased face mask support. A few rales were noted, but his fluid balance was even. A second transfusion reaction was filed with the blood bank and based on the 2 transfusion-associated events with no other clear explanation for his symptoms, the clinical team favored the TRALI diagnosis. However, the blood bank was suspicious this might not be TRALI as the previous night the patient had 2 episodes of respiratory distress with drops in oxygen saturation unassociated with transfusions. The patient was clinically stable for the remainder of the night.

Early the following morning the patient was scheduled for an esophagogastroduodenoscopy to evaluate for a source of his bleeding. At the beginning of the procedure, a unit of washed leukoreduced PRBCs was hung for a Hb level of 6.9 g/dL. No bleeding source was noted in the stomach, but as the endoscope was passed into the duodenum, and after an infusion of only 25 cc of RBCs, the patient became cyanotic and went into cardiac arrest. Despite advanced resuscitation efforts over 90 minutes, the patient could not be successfully resuscitated and died while in the endoscopy suite. A transfusion reaction workup was initiated but was unremarkable. The transfusion medicine staff was suspicious that something other than TRALI was the cause of the patient’s respiratory distress as he had respiratory distress remote to the transfusions and the unit was prepared correctly before administration. The patient’s family agreed to an autopsy.

Pathology

A full autopsy was performed 22 hours after the patient died. The lungs were congested and of increased weight: The right lung was 800 g, and the left was 750 g. The right lower lobe had a wedge-shaped infarction measuring 6 cm × 5 cm fed by a thrombosed vessel. Multiple small hemorrhagic wedge-shaped areas were noted in the left lung. An ulcer measuring 6 cm × 5 cm was noted just distal to the pylorus. At the base of this ulcer was a 1.5 cm × 0.5 cm tract that communicated with the inferior vena cava (Figure 1).

A postmortem blood culture was positive for Clostridium perfringens (C perfringens) and Candida albicans (C Albicans). Interestingly, one of the collected blood culture vials exploded en route to the laboratory, presumably due to the presence of many gas-forming C perfringens bacteria.

On microscopic examination of the autopsy samples, gram-positive rods were observed in the tissue of multiple organs, including the heart, lungs, liver, and kidneys (Figure 2).

Serology

Fourteen days after the patient’s death, both PRBC units infused during transfusion reactions were positive for granulocyte antibodies by immunofluorescence and agglutination techniques. Human leukocyte antigen antibody testing was also sent but was not found in either the donor or patient.

Discussion

Our case illustrates the unique and challenging diagnosis of DCF given the rarity of presentation and how quickly patients may clinically decompensate. After an extensive search of the medical literature, we were only able to identify about 40 previous cases of DCF, of which 37 were described in one review.¹ DCF, although rare, should be considered at risk for forming in the following settings: migrating inferior vena cava filter, right nephrectomy and radiotherapy, duodenal peptic ulcer, abdominal trauma, and oncologic settings involving metastatic malignancy requiring radiation and/or surgical grafting of the inferior vena cava.^1-4 When the diagnosis is considered, computed tomography (CT) is the best initial imaging modality as it allows for noninvasive evaluation of both the inferior vena cava and nonadjacent structures. A commonality of our case and those described in the literature is the diagnostic mystery and nonspecific symptoms patients present with, thus making CT an appropriate diagnostic modality. Endoscopy is useful for the further workup of GI bleeding and the diagnosis of peptic ulcer disease.⁵ In our case, given the patient’s autopsy findings and history of extensive nonsteroidal anti-inflammatory drug use, the duodenal peptic ulcer was likely the precipitating factor for his DCF.

The most challenging aspect in diagnosing DCF is that many times patients present with nonspecific symptoms, and given its rarity it is not something that is usually at the forefront of most differentials.² This diagnostic difficulty may elucidate why there is such a relatively high mortality rate—nearly 40%—associated with DCF and why many times accurate diagnosis is not made until autopsy.^1,3 The most common presenting manifestations are sepsis and/or GI bleeding; in less than half the cases described in the literature patients had both sepsis and GI bleeding. In our case, the patient had signs of melena but was not felt to be septic as his presenting signs were felt to be in the setting of blood loss and dehydration (given his history of bulimia), not an acute infectious source.

In retrospect, one of the more confounding aspects of this case is the clinical picture concerning for TRALI. The patient required supplemental oxygen throughout his hospitalization and decompensated while or after receiving a transfusion, thus having TRALI on the differential was not felt inappropriate at that time. However, this case also illustrates the power of an anchoring bias, and perhaps the clinical team anchored on the diagnosis of TRALI too quickly before considering other possible etiologies for the patient’s respiratory distress. TRALI can be one of the most challenging diagnoses to make in the field of transfusion medicine as there are no definitive diagnostic criteria.⁶ It is felt to be a clinical diagnosis of exclusion as there is no pathognomonic sign or diagnostic test to confirm it as the cause of the patient’s respiratory distress, though anti–human leukocyte antigen antibodies commonly are present.^6,7 Considering how quickly the patient decompensated on day 2 of hospitalization and the presence of C perfringens bacteremia, which carries a mortality rate of 27% to 44%, it is likely that further diagnostic workup would not have changed the clinical outcome.⁸

Conclusions

Our investigation reports a case of a DCF in the setting of significant duodenal peptic ulcer disease. We highlight the diagnostic challenge that this commonly lethal etiology presents. We believe ours is the first case in which it was confused for TRALI and associated with food embolism to the lungs causing hypoxic respiratory failure. We want to highlight that DCF, though rare, should be considered for patients who present with GI bleeding and hypoxic respiratory failure.

A duodenocaval fistula (DCF) is seen when a connection exists between the duodenum and the inferior vena cava. It is a rare entity that is commonly missed and presents a diagnostic challenge due to its nonspecific presenting symptoms.^1,2 Patients commonly present with gastrointestinal (GI) bleeding or sepsis. Here we present a case of a 37-year-old man who presented to the hospital for a workup related to melena but went into cardiac arrest prior to an esophagogastroduodenoscopy. Unfortunately, on autopsy, the patient was found to have a DCF. We highlight the diagnostic challenge associated with DCF and how in this case the presentation was confused by a diagnosis of possible transfusion-related acute lung injury (TRALI). To the best of our knowledge, this is also the first description of a case of DCF associated with food embolism to the lungs causing respiratory failure.

Case Presentation

A 37-year-old man with a history significant for bulimia presented to the hospital with a 3-day history of melena and reports of dizziness. The patient did not report being on any prescribed medications but noted that he took 4 aspirin daily to “calm his nerves.” The rest of the patient’s history was unremarkable aside from a reported history of induced emesis 3 to 4 times per week for an extended period up until 2 weeks before admission.

On admission, his vital signs demonstrated tachycardia and orthostatic hypotension. Pertinent findings on physical examination were skin pallor, a normal lung examination, mild epigastric tenderness, and guaiac-positive stools. He was alert and oriented to person, place, and time with no focal deficits. His admission laboratory tests were notable for a hemoglobin (Hb) level of 4.6 g/dL (reference range, 14-17.9), a white blood cell count of 13.5 K/cm (reference range, 4.5-11), an international normalized ratio of 1.21, a blood urea nitrogen of 61 mg/dL (reference range, 10-20), and a creatinine of 2.3 mg/dL (reference range, 0.8-1.4). The patient was placed on 2 L of oxygen via nasal cannula for comfort rather than true hypoxia. A chest X-ray on admission was negative with no signs of infiltrate, edema, or widened mediastinum. An abdominal X-ray was significant for a dilated stomach consistent with bulimia with no abdominal free air or signs of obstruction. The case was discussed with the gastroenterology service who felt that the patient needed to be more hemodynamically stable before pursuing endoscopic evaluation.

He was admitted to the intensive care unit and give a transfusion of 4 units of fresh frozen plasma and 2 packed red blood cells (PRBCs) without any issues. During the infusion of a third PRBC, he developed chills, tachycardia, and hypertension with accompanying respiratory distress characterized by wheezing, decreased breath sounds bilaterally, and a decrease in oxygen saturation to 70% on 2 L supplemental oxygen. He responded to treatment with meperidine, methylprednisolone sodium succinate, albuterol nebulizer, and acetaminophen. A new chest X-ray was read as “development of pulmonary edema vs bilateral pneumonitis.” A transfusion reaction was reported to the blood bank and a diagnosis of TRALI was considered. That evening, he completed a dose of platelets and another PRBC without difficulty after he was premedicated with meperidine, methylprednisolone sodium succinate, and acetaminophen. During the night, the patient spiked a temperature of 40.3 °C that was successfully treated with a cooling blanket and acetaminophen.

The following morning the patient was found to be tachypneic and tachycardic with his face mask off. His symptoms were corrected by replacing his face mask. He claimed he felt anxious about getting more transfusions and that he had breathing problems like this at home in the recent past. The patient requested an aspirin to calm his nerves. Over the course of the day, his Hb level dropped from 6.6 g/dL to 5.9 g/dL, and 2 washed leukopoor PRBCs were ordered.

The first unit was infused uneventfully, but after 125 cc of the second unit, the patient developed respiratory distress, rigors, and hypotension to 70/58 mm Hg despite premedication. He again was treated successfully with increased face mask support. A few rales were noted, but his fluid balance was even. A second transfusion reaction was filed with the blood bank and based on the 2 transfusion-associated events with no other clear explanation for his symptoms, the clinical team favored the TRALI diagnosis. However, the blood bank was suspicious this might not be TRALI as the previous night the patient had 2 episodes of respiratory distress with drops in oxygen saturation unassociated with transfusions. The patient was clinically stable for the remainder of the night.

Early the following morning the patient was scheduled for an esophagogastroduodenoscopy to evaluate for a source of his bleeding. At the beginning of the procedure, a unit of washed leukoreduced PRBCs was hung for a Hb level of 6.9 g/dL. No bleeding source was noted in the stomach, but as the endoscope was passed into the duodenum, and after an infusion of only 25 cc of RBCs, the patient became cyanotic and went into cardiac arrest. Despite advanced resuscitation efforts over 90 minutes, the patient could not be successfully resuscitated and died while in the endoscopy suite. A transfusion reaction workup was initiated but was unremarkable. The transfusion medicine staff was suspicious that something other than TRALI was the cause of the patient’s respiratory distress as he had respiratory distress remote to the transfusions and the unit was prepared correctly before administration. The patient’s family agreed to an autopsy.

Pathology

A full autopsy was performed 22 hours after the patient died. The lungs were congested and of increased weight: The right lung was 800 g, and the left was 750 g. The right lower lobe had a wedge-shaped infarction measuring 6 cm × 5 cm fed by a thrombosed vessel. Multiple small hemorrhagic wedge-shaped areas were noted in the left lung. An ulcer measuring 6 cm × 5 cm was noted just distal to the pylorus. At the base of this ulcer was a 1.5 cm × 0.5 cm tract that communicated with the inferior vena cava (Figure 1).

A postmortem blood culture was positive for Clostridium perfringens (C perfringens) and Candida albicans (C Albicans). Interestingly, one of the collected blood culture vials exploded en route to the laboratory, presumably due to the presence of many gas-forming C perfringens bacteria.

On microscopic examination of the autopsy samples, gram-positive rods were observed in the tissue of multiple organs, including the heart, lungs, liver, and kidneys (Figure 2).

Serology

Fourteen days after the patient’s death, both PRBC units infused during transfusion reactions were positive for granulocyte antibodies by immunofluorescence and agglutination techniques. Human leukocyte antigen antibody testing was also sent but was not found in either the donor or patient.

Discussion

Our case illustrates the unique and challenging diagnosis of DCF given the rarity of presentation and how quickly patients may clinically decompensate. After an extensive search of the medical literature, we were only able to identify about 40 previous cases of DCF, of which 37 were described in one review.¹ DCF, although rare, should be considered at risk for forming in the following settings: migrating inferior vena cava filter, right nephrectomy and radiotherapy, duodenal peptic ulcer, abdominal trauma, and oncologic settings involving metastatic malignancy requiring radiation and/or surgical grafting of the inferior vena cava.^1-4 When the diagnosis is considered, computed tomography (CT) is the best initial imaging modality as it allows for noninvasive evaluation of both the inferior vena cava and nonadjacent structures. A commonality of our case and those described in the literature is the diagnostic mystery and nonspecific symptoms patients present with, thus making CT an appropriate diagnostic modality. Endoscopy is useful for the further workup of GI bleeding and the diagnosis of peptic ulcer disease.⁵ In our case, given the patient’s autopsy findings and history of extensive nonsteroidal anti-inflammatory drug use, the duodenal peptic ulcer was likely the precipitating factor for his DCF.

The most challenging aspect in diagnosing DCF is that many times patients present with nonspecific symptoms, and given its rarity it is not something that is usually at the forefront of most differentials.² This diagnostic difficulty may elucidate why there is such a relatively high mortality rate—nearly 40%—associated with DCF and why many times accurate diagnosis is not made until autopsy.^1,3 The most common presenting manifestations are sepsis and/or GI bleeding; in less than half the cases described in the literature patients had both sepsis and GI bleeding. In our case, the patient had signs of melena but was not felt to be septic as his presenting signs were felt to be in the setting of blood loss and dehydration (given his history of bulimia), not an acute infectious source.

In retrospect, one of the more confounding aspects of this case is the clinical picture concerning for TRALI. The patient required supplemental oxygen throughout his hospitalization and decompensated while or after receiving a transfusion, thus having TRALI on the differential was not felt inappropriate at that time. However, this case also illustrates the power of an anchoring bias, and perhaps the clinical team anchored on the diagnosis of TRALI too quickly before considering other possible etiologies for the patient’s respiratory distress. TRALI can be one of the most challenging diagnoses to make in the field of transfusion medicine as there are no definitive diagnostic criteria.⁶ It is felt to be a clinical diagnosis of exclusion as there is no pathognomonic sign or diagnostic test to confirm it as the cause of the patient’s respiratory distress, though anti–human leukocyte antigen antibodies commonly are present.^6,7 Considering how quickly the patient decompensated on day 2 of hospitalization and the presence of C perfringens bacteremia, which carries a mortality rate of 27% to 44%, it is likely that further diagnostic workup would not have changed the clinical outcome.⁸

Conclusions

Our investigation reports a case of a DCF in the setting of significant duodenal peptic ulcer disease. We highlight the diagnostic challenge that this commonly lethal etiology presents. We believe ours is the first case in which it was confused for TRALI and associated with food embolism to the lungs causing hypoxic respiratory failure. We want to highlight that DCF, though rare, should be considered for patients who present with GI bleeding and hypoxic respiratory failure.

A duodenocaval fistula (DCF) is seen when a connection exists between the duodenum and the inferior vena cava. It is a rare entity that is commonly missed and presents a diagnostic challenge due to its nonspecific presenting symptoms.^1,2 Patients commonly present with gastrointestinal (GI) bleeding or sepsis. Here we present a case of a 37-year-old man who presented to the hospital for a workup related to melena but went into cardiac arrest prior to an esophagogastroduodenoscopy. Unfortunately, on autopsy, the patient was found to have a DCF. We highlight the diagnostic challenge associated with DCF and how in this case the presentation was confused by a diagnosis of possible transfusion-related acute lung injury (TRALI). To the best of our knowledge, this is also the first description of a case of DCF associated with food embolism to the lungs causing respiratory failure.

Case Presentation

A 37-year-old man with a history significant for bulimia presented to the hospital with a 3-day history of melena and reports of dizziness. The patient did not report being on any prescribed medications but noted that he took 4 aspirin daily to “calm his nerves.” The rest of the patient’s history was unremarkable aside from a reported history of induced emesis 3 to 4 times per week for an extended period up until 2 weeks before admission.

On admission, his vital signs demonstrated tachycardia and orthostatic hypotension. Pertinent findings on physical examination were skin pallor, a normal lung examination, mild epigastric tenderness, and guaiac-positive stools. He was alert and oriented to person, place, and time with no focal deficits. His admission laboratory tests were notable for a hemoglobin (Hb) level of 4.6 g/dL (reference range, 14-17.9), a white blood cell count of 13.5 K/cm (reference range, 4.5-11), an international normalized ratio of 1.21, a blood urea nitrogen of 61 mg/dL (reference range, 10-20), and a creatinine of 2.3 mg/dL (reference range, 0.8-1.4). The patient was placed on 2 L of oxygen via nasal cannula for comfort rather than true hypoxia. A chest X-ray on admission was negative with no signs of infiltrate, edema, or widened mediastinum. An abdominal X-ray was significant for a dilated stomach consistent with bulimia with no abdominal free air or signs of obstruction. The case was discussed with the gastroenterology service who felt that the patient needed to be more hemodynamically stable before pursuing endoscopic evaluation.

He was admitted to the intensive care unit and give a transfusion of 4 units of fresh frozen plasma and 2 packed red blood cells (PRBCs) without any issues. During the infusion of a third PRBC, he developed chills, tachycardia, and hypertension with accompanying respiratory distress characterized by wheezing, decreased breath sounds bilaterally, and a decrease in oxygen saturation to 70% on 2 L supplemental oxygen. He responded to treatment with meperidine, methylprednisolone sodium succinate, albuterol nebulizer, and acetaminophen. A new chest X-ray was read as “development of pulmonary edema vs bilateral pneumonitis.” A transfusion reaction was reported to the blood bank and a diagnosis of TRALI was considered. That evening, he completed a dose of platelets and another PRBC without difficulty after he was premedicated with meperidine, methylprednisolone sodium succinate, and acetaminophen. During the night, the patient spiked a temperature of 40.3 °C that was successfully treated with a cooling blanket and acetaminophen.

The following morning the patient was found to be tachypneic and tachycardic with his face mask off. His symptoms were corrected by replacing his face mask. He claimed he felt anxious about getting more transfusions and that he had breathing problems like this at home in the recent past. The patient requested an aspirin to calm his nerves. Over the course of the day, his Hb level dropped from 6.6 g/dL to 5.9 g/dL, and 2 washed leukopoor PRBCs were ordered.

The first unit was infused uneventfully, but after 125 cc of the second unit, the patient developed respiratory distress, rigors, and hypotension to 70/58 mm Hg despite premedication. He again was treated successfully with increased face mask support. A few rales were noted, but his fluid balance was even. A second transfusion reaction was filed with the blood bank and based on the 2 transfusion-associated events with no other clear explanation for his symptoms, the clinical team favored the TRALI diagnosis. However, the blood bank was suspicious this might not be TRALI as the previous night the patient had 2 episodes of respiratory distress with drops in oxygen saturation unassociated with transfusions. The patient was clinically stable for the remainder of the night.

Early the following morning the patient was scheduled for an esophagogastroduodenoscopy to evaluate for a source of his bleeding. At the beginning of the procedure, a unit of washed leukoreduced PRBCs was hung for a Hb level of 6.9 g/dL. No bleeding source was noted in the stomach, but as the endoscope was passed into the duodenum, and after an infusion of only 25 cc of RBCs, the patient became cyanotic and went into cardiac arrest. Despite advanced resuscitation efforts over 90 minutes, the patient could not be successfully resuscitated and died while in the endoscopy suite. A transfusion reaction workup was initiated but was unremarkable. The transfusion medicine staff was suspicious that something other than TRALI was the cause of the patient’s respiratory distress as he had respiratory distress remote to the transfusions and the unit was prepared correctly before administration. The patient’s family agreed to an autopsy.

Pathology

A full autopsy was performed 22 hours after the patient died. The lungs were congested and of increased weight: The right lung was 800 g, and the left was 750 g. The right lower lobe had a wedge-shaped infarction measuring 6 cm × 5 cm fed by a thrombosed vessel. Multiple small hemorrhagic wedge-shaped areas were noted in the left lung. An ulcer measuring 6 cm × 5 cm was noted just distal to the pylorus. At the base of this ulcer was a 1.5 cm × 0.5 cm tract that communicated with the inferior vena cava (Figure 1).

A postmortem blood culture was positive for Clostridium perfringens (C perfringens) and Candida albicans (C Albicans). Interestingly, one of the collected blood culture vials exploded en route to the laboratory, presumably due to the presence of many gas-forming C perfringens bacteria.

On microscopic examination of the autopsy samples, gram-positive rods were observed in the tissue of multiple organs, including the heart, lungs, liver, and kidneys (Figure 2).

Serology

Fourteen days after the patient’s death, both PRBC units infused during transfusion reactions were positive for granulocyte antibodies by immunofluorescence and agglutination techniques. Human leukocyte antigen antibody testing was also sent but was not found in either the donor or patient.

Discussion

Our case illustrates the unique and challenging diagnosis of DCF given the rarity of presentation and how quickly patients may clinically decompensate. After an extensive search of the medical literature, we were only able to identify about 40 previous cases of DCF, of which 37 were described in one review.¹ DCF, although rare, should be considered at risk for forming in the following settings: migrating inferior vena cava filter, right nephrectomy and radiotherapy, duodenal peptic ulcer, abdominal trauma, and oncologic settings involving metastatic malignancy requiring radiation and/or surgical grafting of the inferior vena cava.^1-4 When the diagnosis is considered, computed tomography (CT) is the best initial imaging modality as it allows for noninvasive evaluation of both the inferior vena cava and nonadjacent structures. A commonality of our case and those described in the literature is the diagnostic mystery and nonspecific symptoms patients present with, thus making CT an appropriate diagnostic modality. Endoscopy is useful for the further workup of GI bleeding and the diagnosis of peptic ulcer disease.⁵ In our case, given the patient’s autopsy findings and history of extensive nonsteroidal anti-inflammatory drug use, the duodenal peptic ulcer was likely the precipitating factor for his DCF.

The most challenging aspect in diagnosing DCF is that many times patients present with nonspecific symptoms, and given its rarity it is not something that is usually at the forefront of most differentials.² This diagnostic difficulty may elucidate why there is such a relatively high mortality rate—nearly 40%—associated with DCF and why many times accurate diagnosis is not made until autopsy.^1,3 The most common presenting manifestations are sepsis and/or GI bleeding; in less than half the cases described in the literature patients had both sepsis and GI bleeding. In our case, the patient had signs of melena but was not felt to be septic as his presenting signs were felt to be in the setting of blood loss and dehydration (given his history of bulimia), not an acute infectious source.

In retrospect, one of the more confounding aspects of this case is the clinical picture concerning for TRALI. The patient required supplemental oxygen throughout his hospitalization and decompensated while or after receiving a transfusion, thus having TRALI on the differential was not felt inappropriate at that time. However, this case also illustrates the power of an anchoring bias, and perhaps the clinical team anchored on the diagnosis of TRALI too quickly before considering other possible etiologies for the patient’s respiratory distress. TRALI can be one of the most challenging diagnoses to make in the field of transfusion medicine as there are no definitive diagnostic criteria.⁶ It is felt to be a clinical diagnosis of exclusion as there is no pathognomonic sign or diagnostic test to confirm it as the cause of the patient’s respiratory distress, though anti–human leukocyte antigen antibodies commonly are present.^6,7 Considering how quickly the patient decompensated on day 2 of hospitalization and the presence of C perfringens bacteremia, which carries a mortality rate of 27% to 44%, it is likely that further diagnostic workup would not have changed the clinical outcome.⁸

Conclusions

Our investigation reports a case of a DCF in the setting of significant duodenal peptic ulcer disease. We highlight the diagnostic challenge that this commonly lethal etiology presents. We believe ours is the first case in which it was confused for TRALI and associated with food embolism to the lungs causing hypoxic respiratory failure. We want to highlight that DCF, though rare, should be considered for patients who present with GI bleeding and hypoxic respiratory failure.

At the onset of the COVID-19 pandemic, patient encounters with the health care system plummeted.^1-3 The perceived increased risk of contracting COVID-19 while obtaining care was thought to be a contributing factor. In outpatient settings, one study noted a 63% decrease in visits to otolaryngology visits in Massachusetts, and another noted a 33% decrease in dental office visits at the onset of the pandemic in 2020 compared with the same time frame in 2019.^2,4 Along with mask mandates and stay-at-home orders, various institutions sought to mitigate the spread of COVID-19 through different protocols, including the use of social distancing, limitation of visitors, and telehealth. Despite some of these measures, nosocomial infections were not uncommon. For example, one hospital in the United Kingdom reported that 15% of COVID-19 inpatient cases in a 6-week period in 2020 were probably or definitely hospital acquired. These patients had a 36% case fatality rate.⁵

Unlike outpatient treatment centers, however, the emergency department (ED) is mandated by the Emergency Medical Treatment and Labor Act to provide a medical screening examination and to stabilize emergency medical conditions to all patients presenting to the ED. Thus, high numbers of undifferentiated and symptomatic patients are forced to congregate in EDs, increasing the risk of transmission of COVID-19. This perception of increased risk led to a 42% decrease in ED visits during March and April 2020 at the onset of the COVID-19 pandemic.¹ Correspondingly, there was a 20% decrease in code stroke activations at a hospital in Canada and a 38% decrease in ST-elevation myocardial infarction activations across 9 United States hospital systems.^6,7

Limited studies have been conducted to date to determine whether contracting COVID-19 while in the ED is a risk. One retrospective case-control study evaluating 39 EDs in the US showed that ED colocation with known patients with COVID-19 was not associated with an increased risk of COVID-19 transmission.⁵ However, this study also recognized that infection control strategies widely varied by location and date.

In this study, we report the incidence of COVID-19 infections within 21 days after the initial visit for symptoms not associated with COVID-19 infection to the Veterans Affairs Greater Los Angeles Healthcare System (VAGLAHS) ED and compared it with that of COVID-19 infections for tests performed within the VAGLAHS.

Program Description

As a quality improvement measure, the VAGLAHS ED instituted multiple protocols to mitigate COVID-19 transmission. Social distancing was instituted in the waiting room to prevent the close congregation of patients, regardless of the reason for visit. A COVID-19 testing tent was located outdoors that was adjacent to the ED and staffed by a dedicated licensed independent practitioner and nurses during business hours. During COVID-19 infection surges, hours were extended to include evenings and weekends to decrease ED exposure of stable but symptomatic patients seeking testing. If patients were felt to require more care, they were referred to the ED.

Patients with specific symptoms noted during triage, such as those associated with COVID-19 diagnosis, respiratory infections, fever, and/or myalgias, were isolated in their own patient room. Electronic tablets were used for persons under investigation and patients with COVID-19 to communicate with family and/or medical staff who did not need to enter the patient’s room. Two-hour disinfection protocols were instituted for high-risk patients who were moved during the course of their treatment (ie, transfer to another bed for admission or discharge). All staff was specifically trained in personal protective equipment (PPE) donning and doffing, and 2-physician airway teams were implemented to ensure proper PPE use and safe COVID-19 intubations.

COVID-19 Infections

Electronic health records of patients who visited the VAGLAHS ED for symptoms not related to COVID-19 were reviewed from June 1, 2020, to June 30, 2021, to determine whether these patients had an increased incidence of confirmed COVID-19 infection within 21 days of the index ED visit. Patients with upper respiratory infection symptoms, such as cough, fever, chills, sore throat, changes to taste or smell, or a confirmed COVID-19 infection on the initial visit were excluded. Patients were considered to have had an ED-acquired COVID-19 infection if they had a positive test within 21 days of visiting the ED for a symptom not related to COVID-19. We report the overall average positivity rate by month of COVID-19 infections 21 days post-ED visit for visits for symptoms not related to COVID-19. 

A total of 8708 patients who came to the ED with symptoms not associated with COVID-19 infection and had a COVID-19 test within 21 days of the ED visit met the inclusion criteria. The overall average positivity rate at the VAGLAHS ED for symptoms not associated with COVID-19 infection was 1.1% from June 1, 2020, to June 30, 2021. The positivity rate by month ranged from 0% to 6.7% for this period (Figure).

Discussion 

Implementing COVID-19 mitigation measures in the VAGLAHS ED helped minimize exposure and subsequent infection of COVID-19 for veterans who visited the VAGLAHS ED with symptoms not associated with COVID-19 infection. Contextualizing this with the overall average monthly positivity rate of veterans in the VAGLAHS catchment area (10.9%) or Los Angeles County (7.9%) between June 1, 2020, to June 30, 2021, veterans who visited the VAGLAHS ED for symptoms not associated with COVID-19 infection were less likely to test positive for COVID-19 within 21 days (1.1%), suggesting that the extensive measures taken at the VAGLAHS ED were effective.⁸

Many health care systems in the US and abroad have experimented with different transmission mitigation strategies in the ED. These tactics have included careful resource allocation when PPE shortages occur, incorporation of airway teams with appropriate safety measures to reduce nosocomial spread to health care workers, and use of a cohorting plan to separate persons under investigation and patients with COVID-19 from other patients.^9-15 Additionally, forward screening areas were incorporated similar to the COVID-19 tent that was instituted at the VAGLAHS ED to manage patients who were referred to the ED for COVID-19 testing during the beginning of the pandemic, which prevented symptomatic patients from congregating with asymptomatic patients.^14,15

Encouragingly, some of these studies reported no cases of nosocomial transmission in the ED.^11,13 In a separate study, 14 clusters of COVID-19 cases were identified at one VA health care system in which nosocomial transmission was suspected, including one in the ED.¹⁶ Using contact tracing, no patients and 9 employees were found to have contracted COVID-19 in that cluster. Overall, among all clusters examined within the health care system, either by contact tracing or by whole-genome sequencing, the authors found that transmission from health care personnel to patients was rare. Despite different methodologies, we also similarly found that ED patients in our VA facility were unlikely to become infected with COVID-19.

While the low incidence of positive COVID-19 tests cannot be attributed to any one method, our data provide a working blueprint for enhanced ED precautions in future surges of COVID-19 or other airborne diseases, including that of future pandemics.

Limitations

Notably, although the VA is the largest health care system in the US, a considerable number of veterans may present to non-VA EDs to seek care, and thus their data are not included here; these veterans may live farther from a VA facility or experience higher barriers to care than veterans who exclusively or almost exclusively seek care within the VA. As a result, we are unable to account for COVID-19 tests completed outside the VA. Moreover, the wild type SARS-CoV-2 virus was dominant during the time frame chosen for this assessment, and data may not be generalizable to other variants (eg, omicron) that are known to be more highly transmissible.¹⁷ Lastly, although our observation was performed at a single VA ED and may not apply to other facilities, especially in light of different mitigation strategies, our findings still provide support for approaches to minimizing patient and staff exposure to COVID-19 in ED settings.

Conclusions

Implementation of COVID-19 mitigation measures in the VAGLAHS ED may have minimized exposure to COVID-19 for veterans who visited the VAGLAHS ED for symptoms not associated with COVID-19 and did not put one at higher risk of contracting COVID-19. Taken together, our data suggest that patients should not avoid seeking emergency care out of fear of contracting COVID-19 if EDs have adequately instituted mitigation techniques.

At the onset of the COVID-19 pandemic, patient encounters with the health care system plummeted.^1-3 The perceived increased risk of contracting COVID-19 while obtaining care was thought to be a contributing factor. In outpatient settings, one study noted a 63% decrease in visits to otolaryngology visits in Massachusetts, and another noted a 33% decrease in dental office visits at the onset of the pandemic in 2020 compared with the same time frame in 2019.^2,4 Along with mask mandates and stay-at-home orders, various institutions sought to mitigate the spread of COVID-19 through different protocols, including the use of social distancing, limitation of visitors, and telehealth. Despite some of these measures, nosocomial infections were not uncommon. For example, one hospital in the United Kingdom reported that 15% of COVID-19 inpatient cases in a 6-week period in 2020 were probably or definitely hospital acquired. These patients had a 36% case fatality rate.⁵

Unlike outpatient treatment centers, however, the emergency department (ED) is mandated by the Emergency Medical Treatment and Labor Act to provide a medical screening examination and to stabilize emergency medical conditions to all patients presenting to the ED. Thus, high numbers of undifferentiated and symptomatic patients are forced to congregate in EDs, increasing the risk of transmission of COVID-19. This perception of increased risk led to a 42% decrease in ED visits during March and April 2020 at the onset of the COVID-19 pandemic.¹ Correspondingly, there was a 20% decrease in code stroke activations at a hospital in Canada and a 38% decrease in ST-elevation myocardial infarction activations across 9 United States hospital systems.^6,7

Limited studies have been conducted to date to determine whether contracting COVID-19 while in the ED is a risk. One retrospective case-control study evaluating 39 EDs in the US showed that ED colocation with known patients with COVID-19 was not associated with an increased risk of COVID-19 transmission.⁵ However, this study also recognized that infection control strategies widely varied by location and date.

In this study, we report the incidence of COVID-19 infections within 21 days after the initial visit for symptoms not associated with COVID-19 infection to the Veterans Affairs Greater Los Angeles Healthcare System (VAGLAHS) ED and compared it with that of COVID-19 infections for tests performed within the VAGLAHS.

Program Description

As a quality improvement measure, the VAGLAHS ED instituted multiple protocols to mitigate COVID-19 transmission. Social distancing was instituted in the waiting room to prevent the close congregation of patients, regardless of the reason for visit. A COVID-19 testing tent was located outdoors that was adjacent to the ED and staffed by a dedicated licensed independent practitioner and nurses during business hours. During COVID-19 infection surges, hours were extended to include evenings and weekends to decrease ED exposure of stable but symptomatic patients seeking testing. If patients were felt to require more care, they were referred to the ED.

Patients with specific symptoms noted during triage, such as those associated with COVID-19 diagnosis, respiratory infections, fever, and/or myalgias, were isolated in their own patient room. Electronic tablets were used for persons under investigation and patients with COVID-19 to communicate with family and/or medical staff who did not need to enter the patient’s room. Two-hour disinfection protocols were instituted for high-risk patients who were moved during the course of their treatment (ie, transfer to another bed for admission or discharge). All staff was specifically trained in personal protective equipment (PPE) donning and doffing, and 2-physician airway teams were implemented to ensure proper PPE use and safe COVID-19 intubations.

COVID-19 Infections

Electronic health records of patients who visited the VAGLAHS ED for symptoms not related to COVID-19 were reviewed from June 1, 2020, to June 30, 2021, to determine whether these patients had an increased incidence of confirmed COVID-19 infection within 21 days of the index ED visit. Patients with upper respiratory infection symptoms, such as cough, fever, chills, sore throat, changes to taste or smell, or a confirmed COVID-19 infection on the initial visit were excluded. Patients were considered to have had an ED-acquired COVID-19 infection if they had a positive test within 21 days of visiting the ED for a symptom not related to COVID-19. We report the overall average positivity rate by month of COVID-19 infections 21 days post-ED visit for visits for symptoms not related to COVID-19. 

A total of 8708 patients who came to the ED with symptoms not associated with COVID-19 infection and had a COVID-19 test within 21 days of the ED visit met the inclusion criteria. The overall average positivity rate at the VAGLAHS ED for symptoms not associated with COVID-19 infection was 1.1% from June 1, 2020, to June 30, 2021. The positivity rate by month ranged from 0% to 6.7% for this period (Figure).

Discussion 

Implementing COVID-19 mitigation measures in the VAGLAHS ED helped minimize exposure and subsequent infection of COVID-19 for veterans who visited the VAGLAHS ED with symptoms not associated with COVID-19 infection. Contextualizing this with the overall average monthly positivity rate of veterans in the VAGLAHS catchment area (10.9%) or Los Angeles County (7.9%) between June 1, 2020, to June 30, 2021, veterans who visited the VAGLAHS ED for symptoms not associated with COVID-19 infection were less likely to test positive for COVID-19 within 21 days (1.1%), suggesting that the extensive measures taken at the VAGLAHS ED were effective.⁸

Many health care systems in the US and abroad have experimented with different transmission mitigation strategies in the ED. These tactics have included careful resource allocation when PPE shortages occur, incorporation of airway teams with appropriate safety measures to reduce nosocomial spread to health care workers, and use of a cohorting plan to separate persons under investigation and patients with COVID-19 from other patients.^9-15 Additionally, forward screening areas were incorporated similar to the COVID-19 tent that was instituted at the VAGLAHS ED to manage patients who were referred to the ED for COVID-19 testing during the beginning of the pandemic, which prevented symptomatic patients from congregating with asymptomatic patients.^14,15

Encouragingly, some of these studies reported no cases of nosocomial transmission in the ED.^11,13 In a separate study, 14 clusters of COVID-19 cases were identified at one VA health care system in which nosocomial transmission was suspected, including one in the ED.¹⁶ Using contact tracing, no patients and 9 employees were found to have contracted COVID-19 in that cluster. Overall, among all clusters examined within the health care system, either by contact tracing or by whole-genome sequencing, the authors found that transmission from health care personnel to patients was rare. Despite different methodologies, we also similarly found that ED patients in our VA facility were unlikely to become infected with COVID-19.

While the low incidence of positive COVID-19 tests cannot be attributed to any one method, our data provide a working blueprint for enhanced ED precautions in future surges of COVID-19 or other airborne diseases, including that of future pandemics.

Limitations

Notably, although the VA is the largest health care system in the US, a considerable number of veterans may present to non-VA EDs to seek care, and thus their data are not included here; these veterans may live farther from a VA facility or experience higher barriers to care than veterans who exclusively or almost exclusively seek care within the VA. As a result, we are unable to account for COVID-19 tests completed outside the VA. Moreover, the wild type SARS-CoV-2 virus was dominant during the time frame chosen for this assessment, and data may not be generalizable to other variants (eg, omicron) that are known to be more highly transmissible.¹⁷ Lastly, although our observation was performed at a single VA ED and may not apply to other facilities, especially in light of different mitigation strategies, our findings still provide support for approaches to minimizing patient and staff exposure to COVID-19 in ED settings.

Conclusions

Implementation of COVID-19 mitigation measures in the VAGLAHS ED may have minimized exposure to COVID-19 for veterans who visited the VAGLAHS ED for symptoms not associated with COVID-19 and did not put one at higher risk of contracting COVID-19. Taken together, our data suggest that patients should not avoid seeking emergency care out of fear of contracting COVID-19 if EDs have adequately instituted mitigation techniques.

At the onset of the COVID-19 pandemic, patient encounters with the health care system plummeted.^1-3 The perceived increased risk of contracting COVID-19 while obtaining care was thought to be a contributing factor. In outpatient settings, one study noted a 63% decrease in visits to otolaryngology visits in Massachusetts, and another noted a 33% decrease in dental office visits at the onset of the pandemic in 2020 compared with the same time frame in 2019.^2,4 Along with mask mandates and stay-at-home orders, various institutions sought to mitigate the spread of COVID-19 through different protocols, including the use of social distancing, limitation of visitors, and telehealth. Despite some of these measures, nosocomial infections were not uncommon. For example, one hospital in the United Kingdom reported that 15% of COVID-19 inpatient cases in a 6-week period in 2020 were probably or definitely hospital acquired. These patients had a 36% case fatality rate.⁵

Unlike outpatient treatment centers, however, the emergency department (ED) is mandated by the Emergency Medical Treatment and Labor Act to provide a medical screening examination and to stabilize emergency medical conditions to all patients presenting to the ED. Thus, high numbers of undifferentiated and symptomatic patients are forced to congregate in EDs, increasing the risk of transmission of COVID-19. This perception of increased risk led to a 42% decrease in ED visits during March and April 2020 at the onset of the COVID-19 pandemic.¹ Correspondingly, there was a 20% decrease in code stroke activations at a hospital in Canada and a 38% decrease in ST-elevation myocardial infarction activations across 9 United States hospital systems.^6,7

Limited studies have been conducted to date to determine whether contracting COVID-19 while in the ED is a risk. One retrospective case-control study evaluating 39 EDs in the US showed that ED colocation with known patients with COVID-19 was not associated with an increased risk of COVID-19 transmission.⁵ However, this study also recognized that infection control strategies widely varied by location and date.

In this study, we report the incidence of COVID-19 infections within 21 days after the initial visit for symptoms not associated with COVID-19 infection to the Veterans Affairs Greater Los Angeles Healthcare System (VAGLAHS) ED and compared it with that of COVID-19 infections for tests performed within the VAGLAHS.

Program Description

As a quality improvement measure, the VAGLAHS ED instituted multiple protocols to mitigate COVID-19 transmission. Social distancing was instituted in the waiting room to prevent the close congregation of patients, regardless of the reason for visit. A COVID-19 testing tent was located outdoors that was adjacent to the ED and staffed by a dedicated licensed independent practitioner and nurses during business hours. During COVID-19 infection surges, hours were extended to include evenings and weekends to decrease ED exposure of stable but symptomatic patients seeking testing. If patients were felt to require more care, they were referred to the ED.

Patients with specific symptoms noted during triage, such as those associated with COVID-19 diagnosis, respiratory infections, fever, and/or myalgias, were isolated in their own patient room. Electronic tablets were used for persons under investigation and patients with COVID-19 to communicate with family and/or medical staff who did not need to enter the patient’s room. Two-hour disinfection protocols were instituted for high-risk patients who were moved during the course of their treatment (ie, transfer to another bed for admission or discharge). All staff was specifically trained in personal protective equipment (PPE) donning and doffing, and 2-physician airway teams were implemented to ensure proper PPE use and safe COVID-19 intubations.

COVID-19 Infections

Electronic health records of patients who visited the VAGLAHS ED for symptoms not related to COVID-19 were reviewed from June 1, 2020, to June 30, 2021, to determine whether these patients had an increased incidence of confirmed COVID-19 infection within 21 days of the index ED visit. Patients with upper respiratory infection symptoms, such as cough, fever, chills, sore throat, changes to taste or smell, or a confirmed COVID-19 infection on the initial visit were excluded. Patients were considered to have had an ED-acquired COVID-19 infection if they had a positive test within 21 days of visiting the ED for a symptom not related to COVID-19. We report the overall average positivity rate by month of COVID-19 infections 21 days post-ED visit for visits for symptoms not related to COVID-19. 

A total of 8708 patients who came to the ED with symptoms not associated with COVID-19 infection and had a COVID-19 test within 21 days of the ED visit met the inclusion criteria. The overall average positivity rate at the VAGLAHS ED for symptoms not associated with COVID-19 infection was 1.1% from June 1, 2020, to June 30, 2021. The positivity rate by month ranged from 0% to 6.7% for this period (Figure).

Discussion 

Implementing COVID-19 mitigation measures in the VAGLAHS ED helped minimize exposure and subsequent infection of COVID-19 for veterans who visited the VAGLAHS ED with symptoms not associated with COVID-19 infection. Contextualizing this with the overall average monthly positivity rate of veterans in the VAGLAHS catchment area (10.9%) or Los Angeles County (7.9%) between June 1, 2020, to June 30, 2021, veterans who visited the VAGLAHS ED for symptoms not associated with COVID-19 infection were less likely to test positive for COVID-19 within 21 days (1.1%), suggesting that the extensive measures taken at the VAGLAHS ED were effective.⁸

Many health care systems in the US and abroad have experimented with different transmission mitigation strategies in the ED. These tactics have included careful resource allocation when PPE shortages occur, incorporation of airway teams with appropriate safety measures to reduce nosocomial spread to health care workers, and use of a cohorting plan to separate persons under investigation and patients with COVID-19 from other patients.^9-15 Additionally, forward screening areas were incorporated similar to the COVID-19 tent that was instituted at the VAGLAHS ED to manage patients who were referred to the ED for COVID-19 testing during the beginning of the pandemic, which prevented symptomatic patients from congregating with asymptomatic patients.^14,15

Encouragingly, some of these studies reported no cases of nosocomial transmission in the ED.^11,13 In a separate study, 14 clusters of COVID-19 cases were identified at one VA health care system in which nosocomial transmission was suspected, including one in the ED.¹⁶ Using contact tracing, no patients and 9 employees were found to have contracted COVID-19 in that cluster. Overall, among all clusters examined within the health care system, either by contact tracing or by whole-genome sequencing, the authors found that transmission from health care personnel to patients was rare. Despite different methodologies, we also similarly found that ED patients in our VA facility were unlikely to become infected with COVID-19.

While the low incidence of positive COVID-19 tests cannot be attributed to any one method, our data provide a working blueprint for enhanced ED precautions in future surges of COVID-19 or other airborne diseases, including that of future pandemics.

Limitations

Notably, although the VA is the largest health care system in the US, a considerable number of veterans may present to non-VA EDs to seek care, and thus their data are not included here; these veterans may live farther from a VA facility or experience higher barriers to care than veterans who exclusively or almost exclusively seek care within the VA. As a result, we are unable to account for COVID-19 tests completed outside the VA. Moreover, the wild type SARS-CoV-2 virus was dominant during the time frame chosen for this assessment, and data may not be generalizable to other variants (eg, omicron) that are known to be more highly transmissible.¹⁷ Lastly, although our observation was performed at a single VA ED and may not apply to other facilities, especially in light of different mitigation strategies, our findings still provide support for approaches to minimizing patient and staff exposure to COVID-19 in ED settings.

Conclusions

Implementation of COVID-19 mitigation measures in the VAGLAHS ED may have minimized exposure to COVID-19 for veterans who visited the VAGLAHS ED for symptoms not associated with COVID-19 and did not put one at higher risk of contracting COVID-19. Taken together, our data suggest that patients should not avoid seeking emergency care out of fear of contracting COVID-19 if EDs have adequately instituted mitigation techniques.