Article

The Diagnosis: Atypical Mycobacterial Infection

The history of rapid growth followed by shrinkage as well as the craterlike clinical appearance of our patient’s lesion were suspicious for the keratoacanthoma variant of squamous cell carcinoma (SCC). Periodic acid–Schiff green staining was negative for fungal or bacterial organisms, and the biopsy findings of keratinocyte atypia and irregular epidermal proliferation seemed to confirm our suspicion for well-differentiated SCC (Figure 1). Our patient subsequently was scheduled for Mohs micrographic surgery. Fortunately, a sample of tissue had been sent for panculture—bacterial, fungal, and mycobacterial—to rule out infectious etiologies, given the history of possible traumatic inoculation, and returned positive for Mycobacterium marinum infection prior to the surgery. Mohs surgery was canceled, and he was referred to an infectious disease specialist who started antibiotic treatment with azithromycin, ethambutol, and rifabutin. After 1 month of treatment the lesion substantially improved (Figure 2), further supporting the diagnosis of M marinum infection over SCC.

The differential diagnosis also included sporotrichosis, leishmaniasis, and chromoblastomycosis. Sporotrichosis lesions typically develop as multiple nodules and ulcers along a path of lymphatic drainage and can exhibit asteroid bodies and cigar-shaped yeast forms on histology. Chromoblastomycosis may display pseudoepitheliomatous hyperplasia and granulomatous inflammation; however, pathognomonic pigmented Medlar bodies also likely would be present.¹ Leishmaniasis has a wide variety of presentations; however, it typically occurs in patients with exposure to endemic areas outside of the United States. Although leishmaniasis may demonstrate pseudoepitheliomatous hyperplasia, ulceration, and mixed inflammation on histology, it also likely would show amastigotes within dermal macrophages.²

Atypical mycobacterial infections initially may be misdiagnosed as SCC due to their tendency to induce irregular acanthosis in the form of pseudoepitheliomatous hyperplasia as well as mild keratinocyte atypia secondary to inflammation.^3,4 Our case is unique because it occurred with M marinum infection specifically. The histopathologic findings of M marinum infections are variable and may additionally include granulomas, most commonly suppurative; intraepithelial abscesses; small vessel proliferation; dermal fibrosis; multinucleated giant cells; and transepidermal elimination.^4,5 Periodic acid–Schiff, Ziehl-Neelsen (acid-fast bacilli), and Fite staining may be used to distinguish M marinum infection from SCC but have low sensitivities (approximately 30%). Culture remains the most reliable test, with a sensitivity of nearly 80%.^5-7 In our patient, a Periodic acid–Schiff stain was obtained prior to receiving culture results, and acid-fast bacilli and Fite staining were added after the culture returned positive; however, all 3 stains failed to highlight any mycobacteria.

The primary risk factor for infection with M marinum is contact with aquatic environments or marine animals, and most cases involve the fingers or the hand.⁶ After we reached the diagnosis and further discussed the patient’s history, he recalled fishing for and cleaning raw shrimp around the time that he had a splinter. The Infectious Diseases Society of America recommends a treatment course extending 1 to 2 months after clinical symptoms resolve with ethambutol in addition to clarithromycin or azithromycin.⁸ If the infection is near a joint, rifampin should be empirically added to account for a potentially deeper infection. Imaging should be obtained to evaluate for joint space involvement, with magnetic resonance imaging being the preferred modality. If joint space involvement is confirmed, surgical debridement is indicated. Surgical debridement also is indicated for infections that fail to respond to antibiotic therapy.⁸

This case highlights M marinum infection as a potential mimicker of SCC, particularly if the biopsy is relatively superficial, as often occurs when obtained via the common shave technique. The distinction is critical, as M marinum infection is highly treatable and inappropriate surgery on the typical hand and finger locations may subject patients to substantial morbidity, such as the need for a skin graft, reduced mobility from scarring, or risk for serious wound infection.⁹ For superficial biopsies of an atypical squamous process, pathologists also may consider routinely recommending tissue culture, especially for hand and finger locations or when a history of local trauma is reported, instead of recommending complete excision or repeat biopsy alone.

The Diagnosis: Atypical Mycobacterial Infection

The history of rapid growth followed by shrinkage as well as the craterlike clinical appearance of our patient’s lesion were suspicious for the keratoacanthoma variant of squamous cell carcinoma (SCC). Periodic acid–Schiff green staining was negative for fungal or bacterial organisms, and the biopsy findings of keratinocyte atypia and irregular epidermal proliferation seemed to confirm our suspicion for well-differentiated SCC (Figure 1). Our patient subsequently was scheduled for Mohs micrographic surgery. Fortunately, a sample of tissue had been sent for panculture—bacterial, fungal, and mycobacterial—to rule out infectious etiologies, given the history of possible traumatic inoculation, and returned positive for Mycobacterium marinum infection prior to the surgery. Mohs surgery was canceled, and he was referred to an infectious disease specialist who started antibiotic treatment with azithromycin, ethambutol, and rifabutin. After 1 month of treatment the lesion substantially improved (Figure 2), further supporting the diagnosis of M marinum infection over SCC.

The differential diagnosis also included sporotrichosis, leishmaniasis, and chromoblastomycosis. Sporotrichosis lesions typically develop as multiple nodules and ulcers along a path of lymphatic drainage and can exhibit asteroid bodies and cigar-shaped yeast forms on histology. Chromoblastomycosis may display pseudoepitheliomatous hyperplasia and granulomatous inflammation; however, pathognomonic pigmented Medlar bodies also likely would be present.¹ Leishmaniasis has a wide variety of presentations; however, it typically occurs in patients with exposure to endemic areas outside of the United States. Although leishmaniasis may demonstrate pseudoepitheliomatous hyperplasia, ulceration, and mixed inflammation on histology, it also likely would show amastigotes within dermal macrophages.²

Atypical mycobacterial infections initially may be misdiagnosed as SCC due to their tendency to induce irregular acanthosis in the form of pseudoepitheliomatous hyperplasia as well as mild keratinocyte atypia secondary to inflammation.^3,4 Our case is unique because it occurred with M marinum infection specifically. The histopathologic findings of M marinum infections are variable and may additionally include granulomas, most commonly suppurative; intraepithelial abscesses; small vessel proliferation; dermal fibrosis; multinucleated giant cells; and transepidermal elimination.^4,5 Periodic acid–Schiff, Ziehl-Neelsen (acid-fast bacilli), and Fite staining may be used to distinguish M marinum infection from SCC but have low sensitivities (approximately 30%). Culture remains the most reliable test, with a sensitivity of nearly 80%.^5-7 In our patient, a Periodic acid–Schiff stain was obtained prior to receiving culture results, and acid-fast bacilli and Fite staining were added after the culture returned positive; however, all 3 stains failed to highlight any mycobacteria.

The primary risk factor for infection with M marinum is contact with aquatic environments or marine animals, and most cases involve the fingers or the hand.⁶ After we reached the diagnosis and further discussed the patient’s history, he recalled fishing for and cleaning raw shrimp around the time that he had a splinter. The Infectious Diseases Society of America recommends a treatment course extending 1 to 2 months after clinical symptoms resolve with ethambutol in addition to clarithromycin or azithromycin.⁸ If the infection is near a joint, rifampin should be empirically added to account for a potentially deeper infection. Imaging should be obtained to evaluate for joint space involvement, with magnetic resonance imaging being the preferred modality. If joint space involvement is confirmed, surgical debridement is indicated. Surgical debridement also is indicated for infections that fail to respond to antibiotic therapy.⁸

This case highlights M marinum infection as a potential mimicker of SCC, particularly if the biopsy is relatively superficial, as often occurs when obtained via the common shave technique. The distinction is critical, as M marinum infection is highly treatable and inappropriate surgery on the typical hand and finger locations may subject patients to substantial morbidity, such as the need for a skin graft, reduced mobility from scarring, or risk for serious wound infection.⁹ For superficial biopsies of an atypical squamous process, pathologists also may consider routinely recommending tissue culture, especially for hand and finger locations or when a history of local trauma is reported, instead of recommending complete excision or repeat biopsy alone.

The Diagnosis: Atypical Mycobacterial Infection

The history of rapid growth followed by shrinkage as well as the craterlike clinical appearance of our patient’s lesion were suspicious for the keratoacanthoma variant of squamous cell carcinoma (SCC). Periodic acid–Schiff green staining was negative for fungal or bacterial organisms, and the biopsy findings of keratinocyte atypia and irregular epidermal proliferation seemed to confirm our suspicion for well-differentiated SCC (Figure 1). Our patient subsequently was scheduled for Mohs micrographic surgery. Fortunately, a sample of tissue had been sent for panculture—bacterial, fungal, and mycobacterial—to rule out infectious etiologies, given the history of possible traumatic inoculation, and returned positive for Mycobacterium marinum infection prior to the surgery. Mohs surgery was canceled, and he was referred to an infectious disease specialist who started antibiotic treatment with azithromycin, ethambutol, and rifabutin. After 1 month of treatment the lesion substantially improved (Figure 2), further supporting the diagnosis of M marinum infection over SCC.

The differential diagnosis also included sporotrichosis, leishmaniasis, and chromoblastomycosis. Sporotrichosis lesions typically develop as multiple nodules and ulcers along a path of lymphatic drainage and can exhibit asteroid bodies and cigar-shaped yeast forms on histology. Chromoblastomycosis may display pseudoepitheliomatous hyperplasia and granulomatous inflammation; however, pathognomonic pigmented Medlar bodies also likely would be present.¹ Leishmaniasis has a wide variety of presentations; however, it typically occurs in patients with exposure to endemic areas outside of the United States. Although leishmaniasis may demonstrate pseudoepitheliomatous hyperplasia, ulceration, and mixed inflammation on histology, it also likely would show amastigotes within dermal macrophages.²

Atypical mycobacterial infections initially may be misdiagnosed as SCC due to their tendency to induce irregular acanthosis in the form of pseudoepitheliomatous hyperplasia as well as mild keratinocyte atypia secondary to inflammation.^3,4 Our case is unique because it occurred with M marinum infection specifically. The histopathologic findings of M marinum infections are variable and may additionally include granulomas, most commonly suppurative; intraepithelial abscesses; small vessel proliferation; dermal fibrosis; multinucleated giant cells; and transepidermal elimination.^4,5 Periodic acid–Schiff, Ziehl-Neelsen (acid-fast bacilli), and Fite staining may be used to distinguish M marinum infection from SCC but have low sensitivities (approximately 30%). Culture remains the most reliable test, with a sensitivity of nearly 80%.^5-7 In our patient, a Periodic acid–Schiff stain was obtained prior to receiving culture results, and acid-fast bacilli and Fite staining were added after the culture returned positive; however, all 3 stains failed to highlight any mycobacteria.

The primary risk factor for infection with M marinum is contact with aquatic environments or marine animals, and most cases involve the fingers or the hand.⁶ After we reached the diagnosis and further discussed the patient’s history, he recalled fishing for and cleaning raw shrimp around the time that he had a splinter. The Infectious Diseases Society of America recommends a treatment course extending 1 to 2 months after clinical symptoms resolve with ethambutol in addition to clarithromycin or azithromycin.⁸ If the infection is near a joint, rifampin should be empirically added to account for a potentially deeper infection. Imaging should be obtained to evaluate for joint space involvement, with magnetic resonance imaging being the preferred modality. If joint space involvement is confirmed, surgical debridement is indicated. Surgical debridement also is indicated for infections that fail to respond to antibiotic therapy.⁸

This case highlights M marinum infection as a potential mimicker of SCC, particularly if the biopsy is relatively superficial, as often occurs when obtained via the common shave technique. The distinction is critical, as M marinum infection is highly treatable and inappropriate surgery on the typical hand and finger locations may subject patients to substantial morbidity, such as the need for a skin graft, reduced mobility from scarring, or risk for serious wound infection.⁹ For superficial biopsies of an atypical squamous process, pathologists also may consider routinely recommending tissue culture, especially for hand and finger locations or when a history of local trauma is reported, instead of recommending complete excision or repeat biopsy alone.

A dermatology resident has more education and experience than a medical student or intern but less than a fellow or attending physician. Because of this position, residents have a unique opportunity to provide feedback and education to those with less knowledge and experience as a teacher and also to provide feedback to their more senior colleagues about their teaching effectiveness while simultaneously learning from them. The reciprocal exchange of information—from patients and colleagues in clinic, co-residents or attendings in lectures, or in other environments such as pathology at the microscope or skills during simulation training sessions—is the cornerstone of medical education. Being able to give effective feedback while also learning to accept it is one of the most vital skills a resident can learn to thrive in medical education.

The importance of feedback cannot be understated. The art of medicine involves the scientific knowledge needed to treat disease, as well as the social ability to educate, comfort, and heal those afflicted. Mastering this art takes a lifetime. The direct imparting of knowledge from those more experienced to those learning occurs via feedback. In addition, the desire to better oneself leads to more satisfaction with work and improved performance.¹ The ability to give and receive feedback is vital for the field of dermatology and medicine in general.

Types and Implementation of Feedback

Feedback comes in many forms and can be classified via different characteristics such as formal vs informal, written vs spoken, real time vs delayed, and single observer vs pooled data. Each style of feedback has positive and negative aspects, and a feedback provider will need to weigh the pros and cons when deciding the most appropriate one. Although there is no one correct way to provide feedback, the literature shows that some forms of feedback may be more effective and better received than others. This can depend on the context of what is being evaluated.

Many dermatology residencies employ formal scheduled feedback as part of their curricula, ensuring that residents will receive feedback at preset time intervals and providing residency directors with information to assess improvement and areas where more growth is needed. The Accreditation Council for Graduate Medical Education provides a reference for programs on how to give this formal standardized feedback in The Milestones Guidebook.² This feedback is a minimum required amount, with a survey of residents showing preference for frequent informal feedback sessions in addition to standardized formal feedback.³ Another study showed that residents want feedback that is confidential, in person, shortly after experiences, and specific to their actions.⁴ Medical students also voiced a need for frequent, transparent, and actionable feedback during protected, predetermined, and communicated times.⁵ Clearly, learners appreciate spoken intentional feedback as opposed to the traditional formal model of feedback.

Finally, a study was performed analyzing how prior generations of physician educators view millennial trainees.⁶ Because most current dermatology residents were born between 1981 and 1996, this study seemed to pinpoint thoughts toward teaching current residents. The study found that although negative judgments such as millennial entitlement (P<.001), impoliteness (P<.001), oversensitivity (P<.001), and inferior work ethic (P<.001) reached significance, millennial ideals of social justice (P<.001) and savviness with technology (P<.001) also were notable. Overall, millennials were thought to be good colleagues (P<.001), were equally competent to more experienced clinicians (P<.001), and would lead medicine to a good future (P=.039).⁶

Identifying and Maximizing the Impact of Feedback

In addition to how and when to provide feedback, there are discrepancies between attending and resident perception of what is considered feedback. This disconnect can be seen in a study of 122 respondents (67 residents and 55 attendings) that showed 31% of attendings reported giving feedback daily, as opposed to only 9% of residents who reported receiving daily feedback.⁴ When feedback is to be performed, it may be important to specifically announce the process so that it can be properly acknowledged.⁷

Beach⁸ provided a systematic breakdown of clinical teaching to those who may be unfamiliar with the process. This method is divided into preclinic, in-clinic, and postclinic strategies to maximize learning. The author recommended establishing the objectives of the rotation from the teacher’s perspective and inquiring about the objectives of the learner. Both perspectives should inform the lessons to be learned; for example, if a medical student expresses specific interest in psoriasis (a well-established part of a medical student curriculum), all efforts should be placed on arranging for that student to see those specific patients. Beach⁸ also recommended providing resources and creating a positive supportive learning environment to better utilize precious clinic time and create investment in all learning parties. The author recommended matching trainees during clinic to competence-specific challenges in clinical practice where appropriate technical skill is needed. Appropriate autonomy also is promoted, as it requires higher levels of learning and knowledge consolidation. Group discussions can be facilitated by asking questions of increasing levels of difficulty as experience increases. Finally, postclinic feedback should be timely and constructive.⁸

One technique discussed by Beach⁸ is the “1-minute preceptor plus” approach. In this approach, the teacher wants to establish 5 “micro-skills” by first getting a commitment, then checking for supportive evidence of this initial plan, teaching a general principle, reinforcing what was properly performed, and correcting errors. The “plus” comes from trying to take that lesson and apply it to a broader concept. Although this concept is meant to be used in a time-limited setting, it can be expanded to larger conversations. A common example could be made when residents teach rotating medical students through direct observation and supervision during clinic. In this hypothetical situation, the resident and medical student see a patient with erythematous silver-scaled plaques on the elbows and knees. During the patient encounter, the student then inquires about any personal history of cardiovascular disease, diabetes mellitus, and hypertension. After leaving the examination room, the medical student asserts the diagnosis is plaque psoriasis because of the physical examination findings and distribution of lesions. A discussion about the relationship between psoriasis and metabolic syndrome commences, emphasizing the pathophysiology of type 1 helper T-cell–mediated and type 17 helper T-cell–mediated inflammation with vascular damage and growth from inflammatory cytokines.⁹ The student subsequently is praised on inquiring about relevant comorbidities, and a relevant journal article is retrieved for the student’s future studies. Teaching points regarding the Koebner phenomenon, such as that it is not an instantaneous process and comes with a differential diagnosis, are then provided.

Situation-Behavior-Impact is another teaching method developed by the Center for Creative Leadership. In this technique, one will identify what specifically happened, how the learner responded, and what occurred because of the response.¹⁰ This technique is exemplified in the following mock conversation between an attending and their resident following a challenging patient situation: “When you walked into the room and asked the patient coming in for a follow-up appointment ‘What brings you in today?,’ they immediately tensed up and responded that you should already know and check your electronic medical record. This tension could be ameliorated by reviewing the patient’s medical record and addressing what they initially presented for, followed by inquiring if there are other skin problems they want to discuss afterwards.” By identifying the cause-and-effect relationship, helpful and unhelpful responses can be identified and ways to mitigate or continue behaviors can be brainstormed.

The Learning Process

Brodell et all¹¹ outlined techniques to augment the education process that are specific to dermatology. They recommended learning general applicable concepts instead of contextless memorization, mnemonic devices to assist memory for associations and lists, and repetition and practice of learned material. For teaching, they divided techniques into Aristotelian or Socratic; Aristotelian teaching is the formal lecture style, whereas Socratic is conversation based. Both have a place in teaching—as fundamental knowledge grows via Aristotelian teaching, critical thinking can be enhanced via the Socratic method. The authors then outlined tips to create the most conducive learning environment for students.¹¹

Feedback is a reciprocal process with information being given and received by both the teacher and the learner. This is paramount because perfecting the art of teaching is a career-long process and can only be achieved via correction of oversights and mistakes. A questionnaire-based study found that when critiquing the teacher, a combination of self-assessment with assessment from learners was effective in stimulating the greatest level of change in the teacher.¹² This finding likely is because the educator was able to see the juxtaposition of how they think they performed with how students interpreted the same situation. Another survey-based study showed that of 68 attending physicians, 28 attendings saw utility in specialized feedback training; an additional 11 attendings agreed with online modules to improve their feedback skills. A recommendation that trainees receive training on the acceptance feedback also was proposed.¹³ Specialized training to give and receive feedback could be initiated for both attending and resident physicians to fully create an environment emphasizing improvement and teamwork.

Final Thoughts

The art of giving and receiving feedback is a deliberate process that develops with experience and training. Because residents are early in their medical career, being familiar with techniques such as those outlined in this article can enhance teaching and the reception of feedback. Residents are in a unique position, as residency itself is a time of dramatic learning and teaching. Providing feedback gives us a way to advance medicine and better ourselves by solidifying good habits and knowledge.

Acknowledgment—I thank Warren R. Heymann, MD (Camden, New Jersey), for assisting in the creation of this topic and reviewing this article.

A dermatology resident has more education and experience than a medical student or intern but less than a fellow or attending physician. Because of this position, residents have a unique opportunity to provide feedback and education to those with less knowledge and experience as a teacher and also to provide feedback to their more senior colleagues about their teaching effectiveness while simultaneously learning from them. The reciprocal exchange of information—from patients and colleagues in clinic, co-residents or attendings in lectures, or in other environments such as pathology at the microscope or skills during simulation training sessions—is the cornerstone of medical education. Being able to give effective feedback while also learning to accept it is one of the most vital skills a resident can learn to thrive in medical education.

The importance of feedback cannot be understated. The art of medicine involves the scientific knowledge needed to treat disease, as well as the social ability to educate, comfort, and heal those afflicted. Mastering this art takes a lifetime. The direct imparting of knowledge from those more experienced to those learning occurs via feedback. In addition, the desire to better oneself leads to more satisfaction with work and improved performance.¹ The ability to give and receive feedback is vital for the field of dermatology and medicine in general.

Types and Implementation of Feedback

Feedback comes in many forms and can be classified via different characteristics such as formal vs informal, written vs spoken, real time vs delayed, and single observer vs pooled data. Each style of feedback has positive and negative aspects, and a feedback provider will need to weigh the pros and cons when deciding the most appropriate one. Although there is no one correct way to provide feedback, the literature shows that some forms of feedback may be more effective and better received than others. This can depend on the context of what is being evaluated.

Many dermatology residencies employ formal scheduled feedback as part of their curricula, ensuring that residents will receive feedback at preset time intervals and providing residency directors with information to assess improvement and areas where more growth is needed. The Accreditation Council for Graduate Medical Education provides a reference for programs on how to give this formal standardized feedback in The Milestones Guidebook.² This feedback is a minimum required amount, with a survey of residents showing preference for frequent informal feedback sessions in addition to standardized formal feedback.³ Another study showed that residents want feedback that is confidential, in person, shortly after experiences, and specific to their actions.⁴ Medical students also voiced a need for frequent, transparent, and actionable feedback during protected, predetermined, and communicated times.⁵ Clearly, learners appreciate spoken intentional feedback as opposed to the traditional formal model of feedback.

Finally, a study was performed analyzing how prior generations of physician educators view millennial trainees.⁶ Because most current dermatology residents were born between 1981 and 1996, this study seemed to pinpoint thoughts toward teaching current residents. The study found that although negative judgments such as millennial entitlement (P<.001), impoliteness (P<.001), oversensitivity (P<.001), and inferior work ethic (P<.001) reached significance, millennial ideals of social justice (P<.001) and savviness with technology (P<.001) also were notable. Overall, millennials were thought to be good colleagues (P<.001), were equally competent to more experienced clinicians (P<.001), and would lead medicine to a good future (P=.039).⁶

Identifying and Maximizing the Impact of Feedback

In addition to how and when to provide feedback, there are discrepancies between attending and resident perception of what is considered feedback. This disconnect can be seen in a study of 122 respondents (67 residents and 55 attendings) that showed 31% of attendings reported giving feedback daily, as opposed to only 9% of residents who reported receiving daily feedback.⁴ When feedback is to be performed, it may be important to specifically announce the process so that it can be properly acknowledged.⁷

Beach⁸ provided a systematic breakdown of clinical teaching to those who may be unfamiliar with the process. This method is divided into preclinic, in-clinic, and postclinic strategies to maximize learning. The author recommended establishing the objectives of the rotation from the teacher’s perspective and inquiring about the objectives of the learner. Both perspectives should inform the lessons to be learned; for example, if a medical student expresses specific interest in psoriasis (a well-established part of a medical student curriculum), all efforts should be placed on arranging for that student to see those specific patients. Beach⁸ also recommended providing resources and creating a positive supportive learning environment to better utilize precious clinic time and create investment in all learning parties. The author recommended matching trainees during clinic to competence-specific challenges in clinical practice where appropriate technical skill is needed. Appropriate autonomy also is promoted, as it requires higher levels of learning and knowledge consolidation. Group discussions can be facilitated by asking questions of increasing levels of difficulty as experience increases. Finally, postclinic feedback should be timely and constructive.⁸

One technique discussed by Beach⁸ is the “1-minute preceptor plus” approach. In this approach, the teacher wants to establish 5 “micro-skills” by first getting a commitment, then checking for supportive evidence of this initial plan, teaching a general principle, reinforcing what was properly performed, and correcting errors. The “plus” comes from trying to take that lesson and apply it to a broader concept. Although this concept is meant to be used in a time-limited setting, it can be expanded to larger conversations. A common example could be made when residents teach rotating medical students through direct observation and supervision during clinic. In this hypothetical situation, the resident and medical student see a patient with erythematous silver-scaled plaques on the elbows and knees. During the patient encounter, the student then inquires about any personal history of cardiovascular disease, diabetes mellitus, and hypertension. After leaving the examination room, the medical student asserts the diagnosis is plaque psoriasis because of the physical examination findings and distribution of lesions. A discussion about the relationship between psoriasis and metabolic syndrome commences, emphasizing the pathophysiology of type 1 helper T-cell–mediated and type 17 helper T-cell–mediated inflammation with vascular damage and growth from inflammatory cytokines.⁹ The student subsequently is praised on inquiring about relevant comorbidities, and a relevant journal article is retrieved for the student’s future studies. Teaching points regarding the Koebner phenomenon, such as that it is not an instantaneous process and comes with a differential diagnosis, are then provided.

Situation-Behavior-Impact is another teaching method developed by the Center for Creative Leadership. In this technique, one will identify what specifically happened, how the learner responded, and what occurred because of the response.¹⁰ This technique is exemplified in the following mock conversation between an attending and their resident following a challenging patient situation: “When you walked into the room and asked the patient coming in for a follow-up appointment ‘What brings you in today?,’ they immediately tensed up and responded that you should already know and check your electronic medical record. This tension could be ameliorated by reviewing the patient’s medical record and addressing what they initially presented for, followed by inquiring if there are other skin problems they want to discuss afterwards.” By identifying the cause-and-effect relationship, helpful and unhelpful responses can be identified and ways to mitigate or continue behaviors can be brainstormed.

The Learning Process

Brodell et all¹¹ outlined techniques to augment the education process that are specific to dermatology. They recommended learning general applicable concepts instead of contextless memorization, mnemonic devices to assist memory for associations and lists, and repetition and practice of learned material. For teaching, they divided techniques into Aristotelian or Socratic; Aristotelian teaching is the formal lecture style, whereas Socratic is conversation based. Both have a place in teaching—as fundamental knowledge grows via Aristotelian teaching, critical thinking can be enhanced via the Socratic method. The authors then outlined tips to create the most conducive learning environment for students.¹¹

Feedback is a reciprocal process with information being given and received by both the teacher and the learner. This is paramount because perfecting the art of teaching is a career-long process and can only be achieved via correction of oversights and mistakes. A questionnaire-based study found that when critiquing the teacher, a combination of self-assessment with assessment from learners was effective in stimulating the greatest level of change in the teacher.¹² This finding likely is because the educator was able to see the juxtaposition of how they think they performed with how students interpreted the same situation. Another survey-based study showed that of 68 attending physicians, 28 attendings saw utility in specialized feedback training; an additional 11 attendings agreed with online modules to improve their feedback skills. A recommendation that trainees receive training on the acceptance feedback also was proposed.¹³ Specialized training to give and receive feedback could be initiated for both attending and resident physicians to fully create an environment emphasizing improvement and teamwork.

Final Thoughts

The art of giving and receiving feedback is a deliberate process that develops with experience and training. Because residents are early in their medical career, being familiar with techniques such as those outlined in this article can enhance teaching and the reception of feedback. Residents are in a unique position, as residency itself is a time of dramatic learning and teaching. Providing feedback gives us a way to advance medicine and better ourselves by solidifying good habits and knowledge.

Acknowledgment—I thank Warren R. Heymann, MD (Camden, New Jersey), for assisting in the creation of this topic and reviewing this article.

A dermatology resident has more education and experience than a medical student or intern but less than a fellow or attending physician. Because of this position, residents have a unique opportunity to provide feedback and education to those with less knowledge and experience as a teacher and also to provide feedback to their more senior colleagues about their teaching effectiveness while simultaneously learning from them. The reciprocal exchange of information—from patients and colleagues in clinic, co-residents or attendings in lectures, or in other environments such as pathology at the microscope or skills during simulation training sessions—is the cornerstone of medical education. Being able to give effective feedback while also learning to accept it is one of the most vital skills a resident can learn to thrive in medical education.

The importance of feedback cannot be understated. The art of medicine involves the scientific knowledge needed to treat disease, as well as the social ability to educate, comfort, and heal those afflicted. Mastering this art takes a lifetime. The direct imparting of knowledge from those more experienced to those learning occurs via feedback. In addition, the desire to better oneself leads to more satisfaction with work and improved performance.¹ The ability to give and receive feedback is vital for the field of dermatology and medicine in general.

Types and Implementation of Feedback

Feedback comes in many forms and can be classified via different characteristics such as formal vs informal, written vs spoken, real time vs delayed, and single observer vs pooled data. Each style of feedback has positive and negative aspects, and a feedback provider will need to weigh the pros and cons when deciding the most appropriate one. Although there is no one correct way to provide feedback, the literature shows that some forms of feedback may be more effective and better received than others. This can depend on the context of what is being evaluated.

Many dermatology residencies employ formal scheduled feedback as part of their curricula, ensuring that residents will receive feedback at preset time intervals and providing residency directors with information to assess improvement and areas where more growth is needed. The Accreditation Council for Graduate Medical Education provides a reference for programs on how to give this formal standardized feedback in The Milestones Guidebook.² This feedback is a minimum required amount, with a survey of residents showing preference for frequent informal feedback sessions in addition to standardized formal feedback.³ Another study showed that residents want feedback that is confidential, in person, shortly after experiences, and specific to their actions.⁴ Medical students also voiced a need for frequent, transparent, and actionable feedback during protected, predetermined, and communicated times.⁵ Clearly, learners appreciate spoken intentional feedback as opposed to the traditional formal model of feedback.

Finally, a study was performed analyzing how prior generations of physician educators view millennial trainees.⁶ Because most current dermatology residents were born between 1981 and 1996, this study seemed to pinpoint thoughts toward teaching current residents. The study found that although negative judgments such as millennial entitlement (P<.001), impoliteness (P<.001), oversensitivity (P<.001), and inferior work ethic (P<.001) reached significance, millennial ideals of social justice (P<.001) and savviness with technology (P<.001) also were notable. Overall, millennials were thought to be good colleagues (P<.001), were equally competent to more experienced clinicians (P<.001), and would lead medicine to a good future (P=.039).⁶

Identifying and Maximizing the Impact of Feedback

In addition to how and when to provide feedback, there are discrepancies between attending and resident perception of what is considered feedback. This disconnect can be seen in a study of 122 respondents (67 residents and 55 attendings) that showed 31% of attendings reported giving feedback daily, as opposed to only 9% of residents who reported receiving daily feedback.⁴ When feedback is to be performed, it may be important to specifically announce the process so that it can be properly acknowledged.⁷

Beach⁸ provided a systematic breakdown of clinical teaching to those who may be unfamiliar with the process. This method is divided into preclinic, in-clinic, and postclinic strategies to maximize learning. The author recommended establishing the objectives of the rotation from the teacher’s perspective and inquiring about the objectives of the learner. Both perspectives should inform the lessons to be learned; for example, if a medical student expresses specific interest in psoriasis (a well-established part of a medical student curriculum), all efforts should be placed on arranging for that student to see those specific patients. Beach⁸ also recommended providing resources and creating a positive supportive learning environment to better utilize precious clinic time and create investment in all learning parties. The author recommended matching trainees during clinic to competence-specific challenges in clinical practice where appropriate technical skill is needed. Appropriate autonomy also is promoted, as it requires higher levels of learning and knowledge consolidation. Group discussions can be facilitated by asking questions of increasing levels of difficulty as experience increases. Finally, postclinic feedback should be timely and constructive.⁸

One technique discussed by Beach⁸ is the “1-minute preceptor plus” approach. In this approach, the teacher wants to establish 5 “micro-skills” by first getting a commitment, then checking for supportive evidence of this initial plan, teaching a general principle, reinforcing what was properly performed, and correcting errors. The “plus” comes from trying to take that lesson and apply it to a broader concept. Although this concept is meant to be used in a time-limited setting, it can be expanded to larger conversations. A common example could be made when residents teach rotating medical students through direct observation and supervision during clinic. In this hypothetical situation, the resident and medical student see a patient with erythematous silver-scaled plaques on the elbows and knees. During the patient encounter, the student then inquires about any personal history of cardiovascular disease, diabetes mellitus, and hypertension. After leaving the examination room, the medical student asserts the diagnosis is plaque psoriasis because of the physical examination findings and distribution of lesions. A discussion about the relationship between psoriasis and metabolic syndrome commences, emphasizing the pathophysiology of type 1 helper T-cell–mediated and type 17 helper T-cell–mediated inflammation with vascular damage and growth from inflammatory cytokines.⁹ The student subsequently is praised on inquiring about relevant comorbidities, and a relevant journal article is retrieved for the student’s future studies. Teaching points regarding the Koebner phenomenon, such as that it is not an instantaneous process and comes with a differential diagnosis, are then provided.

Situation-Behavior-Impact is another teaching method developed by the Center for Creative Leadership. In this technique, one will identify what specifically happened, how the learner responded, and what occurred because of the response.¹⁰ This technique is exemplified in the following mock conversation between an attending and their resident following a challenging patient situation: “When you walked into the room and asked the patient coming in for a follow-up appointment ‘What brings you in today?,’ they immediately tensed up and responded that you should already know and check your electronic medical record. This tension could be ameliorated by reviewing the patient’s medical record and addressing what they initially presented for, followed by inquiring if there are other skin problems they want to discuss afterwards.” By identifying the cause-and-effect relationship, helpful and unhelpful responses can be identified and ways to mitigate or continue behaviors can be brainstormed.

The Learning Process

Brodell et all¹¹ outlined techniques to augment the education process that are specific to dermatology. They recommended learning general applicable concepts instead of contextless memorization, mnemonic devices to assist memory for associations and lists, and repetition and practice of learned material. For teaching, they divided techniques into Aristotelian or Socratic; Aristotelian teaching is the formal lecture style, whereas Socratic is conversation based. Both have a place in teaching—as fundamental knowledge grows via Aristotelian teaching, critical thinking can be enhanced via the Socratic method. The authors then outlined tips to create the most conducive learning environment for students.¹¹

Feedback is a reciprocal process with information being given and received by both the teacher and the learner. This is paramount because perfecting the art of teaching is a career-long process and can only be achieved via correction of oversights and mistakes. A questionnaire-based study found that when critiquing the teacher, a combination of self-assessment with assessment from learners was effective in stimulating the greatest level of change in the teacher.¹² This finding likely is because the educator was able to see the juxtaposition of how they think they performed with how students interpreted the same situation. Another survey-based study showed that of 68 attending physicians, 28 attendings saw utility in specialized feedback training; an additional 11 attendings agreed with online modules to improve their feedback skills. A recommendation that trainees receive training on the acceptance feedback also was proposed.¹³ Specialized training to give and receive feedback could be initiated for both attending and resident physicians to fully create an environment emphasizing improvement and teamwork.

Final Thoughts

The art of giving and receiving feedback is a deliberate process that develops with experience and training. Because residents are early in their medical career, being familiar with techniques such as those outlined in this article can enhance teaching and the reception of feedback. Residents are in a unique position, as residency itself is a time of dramatic learning and teaching. Providing feedback gives us a way to advance medicine and better ourselves by solidifying good habits and knowledge.

Acknowledgment—I thank Warren R. Heymann, MD (Camden, New Jersey), for assisting in the creation of this topic and reviewing this article.

OBG Management caught up with Drs. Jan Shifren and Genevieve Neal-Perry while they were attending the annual meeting of The North American Menopause Society (NAMS), held October 12-15, 2022, in Atlanta, Georgia. Dr. Shifren presented on the “Ins and Outs of Hormone Therapy,” while Dr. Neal-Perry focused on “Menopause Physiology.” 

Evaluating symptomatic patients for appropriate hormone therapy

OBG Management: In your presentation to the group at the NAMS meeting, you described a 51-year-old patient with the principal symptoms of frequent hot flashes and night sweats, sleep disruption, fatigue, irritability, vaginal dryness, and dyspareunia. As she reported already trying several lifestyle modification approaches, what are your questions for her to determine whether hormone therapy (HT), systemic or low-dose vaginal, is advisable?

Jan Shifren, MD: As with every patient, you need to begin with a thorough history and confirm her physical exam is up to date. If there are concerns related to genitourinary symptoms of menopause (GSM), then a pelvic exam is indicated. This patient is a healthy menopausal woman with bothersome hot flashes, night sweats, and vaginal dryness. Sleep disruption from night sweats is likely the cause of her fatigue and irritability, and her dyspareunia due to atrophic vulvovaginal changes. The principal indication for systemic HT is bothersome vasomotor symptoms (VMS), and a healthy woman who is under age 60 or within 10 years of the onset of menopause is generally a very good candidate for hormones. For this healthy 51-year-old with bothersome VMS unresponsive to lifestyle modification, the benefits of HT should outweigh potential risks. As low-dose vaginal estrogen therapy is minimally absorbed and very safe, this would be recommended instead of systemic HT if her only menopause symptoms were vaginal dryness and dyspareunia.

HT types and formulations

OBG Management: For this patient, low-dose vaginal estrogen is appropriate. In general, how do you decide on recommendations for combination therapy or estrogen only, and what formulations and dosages do you recommend?

Dr. Shifren: Any woman with a uterus needs to take a progestogen together with estrogen to protect her uterus from estrogen-induced endometrial overgrowth. With low dose vaginal estrogen therapy, however, concurrent progestogen is not needed.

Continue to: Estrogen options...

Many of our patients like the idea that they are using “natural” HT. I inform them that bioidentical is a marketing term rather than a medical term, but if their goal is to take the same hormones that their ovaries made when they were younger, they should use FDA-approved formulations of estradiol and progesterone for their menopausal HT symptoms. I do not recommend compounded bioidentical HT due to concerns regarding product quality and safety. The combination of FDA-approved estradiol patches and oral micronized progesterone provides a high quality, carefully regulated bioidentical HT regimen. For women greatly preferring an oral estrogen, oral estradiol with micronized progesterone is an option.

In addition to patient preference for natural HT, the reasons that I encourage women to consider the estradiol transdermal patch for their menopausal HT include:

1. no increased risk of venous thromboembolic events when physiologically dosed menopausal estradiol therapy is provided by a skin patch (observational data).¹ With oral estrogens, even when dosed for menopause, VTE risk increases, as coagulation factors increase due to the first-pass hepatic effect. This does not occur with non-oral menopausal estrogens.
2. no increased risk of gallbladder disease, which occurs with oral estrogen therapy (observational data)²
3. possibly lower risk of stroke when low-dose menopausal HT is provided via skin patch (observational data)³
4. convenience—the patches are changed once or twice weekly
5. wide range of doses available, which optimizes identifying the lowest effective dose and decreasing the dose over time.

Progestogen options. Progestogens may be given daily or cyclically. Use of daily progestogen typically results in amenorrhea, which is preferred by most women. Cyclic use of a progestogen for 12-14 days each month results in a monthly withdrawal bleed, which is a good option for a woman experiencing bothersome breakthrough bleeding with daily progestogen. Use of a progestogen-releasing IUD is an off-label alternative for endometrial protection with menopausal HT. As discussed earlier, as many women prefer bioidentical HT, one of our preferred regimens is to provide transdermal estradiol with FDA-approved oral micronized progesterone. There are several patches that combine estradiol with a progestogen, but there is not a lot of dosing flexibility and product choice. There also is an approved product available that combines oral estradiol and micronized progesterone in one tablet.

Scheduling follow-up

OBG Management: Now that you have started the opening case patient on HT, how often are you going to monitor her for treatment?

Dr. Shifren: Women will not experience maximum efficacy for hot flash relief from their estrogen therapy for 3 months, so I typically see a patient back at 3 to 4 months to assess side effects and symptom control. I encourage women to reach out sooner if they are having a bothersome side effect. Once she is doing well on an HT regimen, we assess risks and benefits of ongoing treatment annually. The goal is to be certain she is on the lowest dose of estrogen that treats her symptoms, and we slowly decrease the estrogen dose over time.

Breast cancer risk

OBG Management: In your presentation, you mentioned that the risk of breast cancer does not increase appreciably with short-term use of HT. Is it possible to define short term?

Dr. Shifren: In the Women’s Health Initiative (WHI), a large double-blind, randomized, placebo-controlled trial of menopausal HT, there was a slight increase in breast cancer risk after approximately 4 to 5 years of use in women using estrogen with progestogen.⁴ I share with patients that this increased risk is about the same as that of obesity or drinking more than 1 alcoholic beverage daily. As an increased risk of breast cancer does not occur for several years, a woman may be able to take hormones for bothersome symptoms, feel well, and slowly come off without incurring significant breast cancer risk. In the WHI, there was no increase in breast cancer risk in women without a uterus randomized to estrogen alone.

Regarding cardiovascular risk, in the WHI, an increased risk of cardiovascular events generally was not seen in healthy women younger than age 60 and within 10 years of the onset of menopause.⁵ Benefits of HT may not outweigh risks for women with significant underlying cardiovascular risk factors, even if they are younger and close to menopause onset.

Continue to: The importance of shared decision making...

 

 

The importance of shared decision making

Dr. Shifren: As with any important health care decision, women should be involved in an individualized discussion of risks and benefits, with shared decision making about whether HT is the right choice. Women also should be involved in ongoing decisions regarding HT formulation, dose, and duration of use.

A nonhormonal option for hot flashes

OBG Management: How many women experience VMS around the time of menopause?

Dr. Genevieve Neal-Perry, MD, PhD: About 60% to 70% of individuals will experience hot flashes around the time of the menopause.⁶ Of those, about 40% are what we would call moderate to severe hot flashes—which are typically the most disruptive in terms of quality of life.⁷ The window of time in which they are likely to have them, at typically their most intense timeframe, is 2 years before the final menstrual period and the year after.⁷ In terms of the average duration, however, it’s about 7 years, which is a lot longer than what we previously thought.⁸ Moreover, there are disparities in that women of color, particularly African American women, can have them as long as 10 years.⁸
 

OBG Management: Can you explain why the VMS occur, and specifically around the time of menopause?

Dr. Neal-Perry: For many years we did not understand the basic biology of hot flashes. When you think about it, it’s completely amazing—when half of our population experiences hot flashes, and we don’t understand why, and we don’t have therapy that specifically targets hot flashes.

What we now know from work completed by Naomi Rance, in particular, is that a specific region of the brain, the hypothalamus, exhibited changes in number of neurons that seemed to be increased in size in menopausal people and smaller in size in people who were not menopausal.⁹ That started the journey to understanding the biology, and eventual mechanism, of hot flashes. It took about 10-15 years before we really began to understand why.

What we know now is that estrogen, a hormone that is made by the ovaries, activates and inactivates neurons located in the hypothalamus, a brain region that controls our thermoregulation—the way your body perceives temperature. The hypothalamus controls your response to temperature, either you experience chills or you dissipate heat by vasodilating (hot flush) and sweating.

The thermoregulatory region of the hypothalamus houses cells that receive messages from KNDy neurons, neurons also located in the hypothalamus that express kisspeptin, neurokinin, and dynorphin. Importantly, KNDy neurons express estrogen receptors. (The way that I like to think about estrogen and estrogen receptors is that estrogen is like the ball and the receptor is like the catcher’s mitt.) When estrogen interacts with this receptor, it keeps KNDy neurons quiet. But the increased variability and loss of estrogen that occurs around the time of menopause “disinhibits” KNDy neurons—meaning that they are no longer being reined in by estrogen. In response to decreased estrogen regulation, KNDy neurons become hypertrophied with neurotransmitters and more active. Specifically, KNDy neurons release neurokinin, a neuropeptide that self-stimulates KNDy neurons and activates neurons in the thermoregulatory zone of the brain—it’s a speed-forward feed-backward mechanism. The thermoregulatory neurons interpret this signal as “I feel hot,” and the body begins a series of functions to cool things down.

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Continue to: Treatments that act on the thermoregulatory region

 

 

Treatments that act on the thermoregulatory region

Dr. Neal-Perry: I have described what happens in the brain around the time of menopause, and what triggers those hot flashes.

Estrogen. The reason that estrogen worked to treat the hot flashes is because estrogen inhibits and calms the neurons that become hyperactive during the menopause.

Fezolinetant. Fezolinetant is unique because it specifically targets the hormone receptor that triggers hot flashes, the neurokinin receptor. Fezolinetant is a nonhormone therapy that not only reduces the activity of KNDy neurons but also blocks the effects of neurons in the thermoregulatory zone, thereby reducing the sensation of the hot flashes. We are in such a special time in medical history for individuals who experience hot flashes because now we understand the basic biology of hot flashes, and we can generate targeted therapy to manage hot flashes—that is for both individuals who identify as women and individuals who identify as men, because both experience hot flashes.
 

OBG Management: Is there a particular threshold of hot flash symptoms that is considered important to treat, or is treatment based on essentially the bother to patients?

Dr. Neal-Perry: Treatment is solely based on if it bothers the patient. But we do know that people who have lots of bothersome hot flashes have a higher risk for heart disease and may have sleep disruption, reduced cognitive function, and poorer quality of life. Sleep dysfunction can impact the ability to think and function and can put those affected at increased risk for accidents.

For people who are having these symptoms that are disruptive to their life, you do want to treat them. You might say, “Well, we’ve had estrogen, why not use estrogen,” right? Well estrogen works very well, but there are lots of people who can’t use estrogen—individuals who have breast cancer, blood clotting disorders, significant heart disease, or diabetes. Then there are just some people who don’t feel comfortable using estrogen.

We have had a huge gap in care for individuals who experience hot flashes and who are ineligible for menopausal HT. While there are other nonhormonal options, they often have side effects like sexual dysfunction, hypersomnolence, or insomnia. Some people choose not to use these nonhormonal treatments because the side effects are worse for them than to trying to manage the hot flashes. The introduction to a nonhormonal therapy that is effective and does not have lots of side effects is exciting and will be welcomed by many who have not found relief.
 

OBG Management: Is fezolinetant available now for patients?

Dr. Neal-Perry: It is not available yet. Hopefully, it will be approved within the next year. Astellas recently completed a double blind randomized cross over design phase 3 study that found fezolinetant is highly effective for the management of hot flashes and that it has a low side effect profile.¹⁰ Fezolinetant’s most common side effect was COVID-19, a reflection of the fact that the trial was done during the COVID pandemic. The other most common side effect was headache. Everything else was minimal.

Other drugs in the same class as fezolinetant have been under development for the management of hot flashes; however, they encountered liver function challenges, and studies were stopped. Fezolinetant did not cause liver dysfunction.

Hot flash modifiers

OBG Management: Referring to that neuropathway, are there physiologic differences among women who do and do not experience hot flashes, and are there particular mechanisms that may protect patients against being bothered by hot flashes?

Dr. Neal-Perry: Well, there are some things that we can control, and there are things that we cannot control (like our genetic background). Some of the processes that are important for estrogen receptor function and estrogen metabolism, as well as some other receptor systems, can work differently. When estrogen metabolism is slightly different, it could result in reduced estrogen receptor activity and more hot flashes. Then there are some receptor polymorphisms that can increase or reduce the risk for hot flashes—the genetic piece.¹¹

There are things that can modify your risk for hot flashes and the duration of hot flashes. Individuals who are obese or smoke may experience more hot flashes. Women of color, especially African American women, tend to have hot flashes occur earlier in their reproductive life and last for a longer duration; hot flashes may occur up to 2 years before menopause, last for more than 10 years, and be more disruptive. By contrast, Asian women tend to report fewer and less disruptive hot flashes.⁸
 

OBG Management: If fezolinetant were to be FDA approved, will there be particular patients that it will most appropriate for, since it is an estrogen alternative?

Dr. Neal-Perry: Yes, there may be different patients who might benefit from fezolinetant. This will depend on what the situation is—patients who have breast cancer, poorly controlled diabetes, or heart disease, and those patients who prefer not to use estrogen will benefit from fezolinetant, as we are going to look for other treatment options for those individuals. It will be important for medical providers to listen to their patients and understand the medical background of that individual to really define what is the best next step for the management of their hot flashes.

This is an exciting time for individuals affected by menopausal hot flashes; to understand the biology of hot flashes gives us real opportunities to bridge gaps around how to manage them. Individuals who experience hot flashes will know that they don’t have to suffer, that there are other options that are safe, that can help meet their needs and put them in a better place. ●

Multiethnic differences in the menopause experience

---

Excerpted from the presentation, “Do you see me? Culturally responsive care in menopause,” by Makeba Williams, MD, NCMP, at The North American Menopause Society meeting in Atlanta, Georgia, October 12-15, 2022.

Dr. Williams is Vice Chair of Professional Development and Wellness, Associate Professor, Washington University School of Medicine

The Study of Women’s Health Across the Nation (SWAN) challenged the notion that there is a universal menopausal experience.¹ Up until that time, we had been using this universal experience that is based largely on the experiences of White women and applying that data to the experiences of women of color. Other research has shown that African American women have poorer quality of life and health status, and that they receive less treatment for a number of conditions.^2,3

In a recent review of more than 20 years of literature, we found only 17 articles that met the inclusion criteria, reflecting the invisibility of African American women and other ethnic and racial minorities in the menopause literature and research. Key findings included that African American women^1,4:

• experience an earlier age of onset of menopause
• have higher rates of premature menopause and early menopause, which is a risk factor for cardiovascular disease
• experience a longer time of the menopausal transition, with variability in the average age of menopause onset
• overall report lower rates of vaginal symptoms
• are less likely to report sleep disturbances than White women or Hispanic women, but more likely to report these symptoms than Asian women
• experience a higher prevalence, frequency, and severity of vasomotor symptoms (VMS), and were more bothered by those symptoms

− 48.4 years in the Healthy Women’s Study

− 50.9 years in the Penn Ovarian Aging Study

− 51.4 years in SWAN

• reported lower educational attainment, experiencing more socioeconomic disadvantage and exposure to more adverse life effects
• receive less treatment for VMS, hypertension, and depression, and are less likely to be prescribed statin drugs
• experience more discrimination
• use cigarettes and tobacco more, but are less likely to use alcohol and less likely to have physical activity.

Cultural influences on menopause

Im and colleagues have published many studies looking at cultural influences on African American, Hispanic, and Asian American women, and comparing them to White women.⁵ Notable differences were found regarding education level, family income, employment, number of children, and greater perceived health (which is associated with fewer menopausal symptoms). They identified 5 qualitative ideas:

1. Positive acceptance. Minority women, or racial and ethnic women, perceived the transition to menopause more positively, and generally took on a posture of acceptance, reporting feeling liberated from many of the challenges associated with the reproductive period. In addition, many associated a greater sense of maturity and respect within their communities with the natural aging process.
2. Optimism. Ethnic women tended to embrace menopause, using humor and laughter to express emotions during stressful life changes. This runs counter to many of the perspectives reported by White women, who often viewed the menopausal transition and aging negatively, as we equate aging with the loss of youthfulness in the United States.
3. Unique, not universal. Most of the ethnic minority women thought that there was something unique about their menopausal experiences, and that they were influenced by immigration transition, financial situations, etc. Many White woman perceived that the menopausal experience was shared among all women.
4. Closed, not open. There were differences in how we talk about symptoms, or whether or not we talk about them at all. Ethnic women tended to be silent about their symptoms. By contrast, White women tended to be more open and talkative and communicative about their symptoms.
5. Minimizing, not controlling. No symptom management was the strategy of choice for most women. Minority women tended to manage their symptoms by tolerating and normalizing them. Only those women with the most serious symptoms sought out medication for temporary relief. Some expressed a tendency to downplay their symptoms because many of them had more important things that they were dealing with in their lives.

What is an individual social identity?

An individual social identity reflects the many groups to which one belongs. It is how one shows up, and yet it is much more than how they physically show up. When you pass your eye on patients, you are only seeing the tip of the iceberg. The full social identity of a patient resides below the surface. Social identity is complex, on a continuum, and can change depending on time and place. How we prioritize our social identities may change, depending on the context and the situation.

Our intersecting social identities give rise to our cultural identity, and it is through the prism of intersectionality that we can understand the ways in which our social identities converge to give rise to disparities in health care in midlife and menopausal women. Holding space for cultural identity, we can impact how our patients are perceiving their menopause, how they are moving through decision making about taking care of themselves in menopause. And we can provide more responsive care to their cultural identities, and hopefully at the end of the day we reduce some of these disparities that we are seeing in our menopausal patients and also are reducing our unconscious bias in our patient interactions.

Culturally responsive care

There are several components to home in on when we are trying to provide culturally responsive care to patients.

1. A commitment to being culturally curious. We have to accept what the literature is sharing with us, that there is not a universal menopausal experience. We have for far too long applied this universal experience of menopause that has largely been based on White women to different racial and ethnic populations.
2. Recognizing. I appreciate that my identity as a Black woman may be very different from other Black women in the room, or whatever their social identity. I am not expected to understand all of the others’ experiences, and I don’t expect that for you either.
3. Acknowledge unconscious implicit biases. Acknowledge the groups to which you have a strong implicit bias, and allow it to drive you to reduce barriers to engaging with patients.
4. Connecting with the individual patient. It is through a process of individuating that we learn from our patients’ unique characteristics, rather than relying on assumptions and stereotypes. We have a window of opportunity to see our patient and move beyond thinking of them in terms of racial and ethnic stereotypes or particular social groups. It is through this process of individualizing that we can seek answers to key questions.

The ultimate goal is to understand our individual patients’ perceptions, outlook on menopause, and contextual factors in their lives that influence the menopause journey.

CASE ENCOUNTER

I quickly look at the patient-filled form before I knock on the exam door, and I see that the patient has checked off that she has hot flashes, night sweats, and I make a mental note, she’s menopausal. I already have a preliminary plan to give this patient hormone therapy. I open the door, and I see that she’s Black. I know, based upon the data from SWAN and others, that her menopause means longer duration, more severe vasomotor symptoms. I have already teed up a prescription to go to the pharmacy.

The problem is, I have not even talked to her. She may actually nod her head, saying that she is going to go to the pharmacy, but she may never pick up that prescription. She likely leaves my office feeling unheard; her needs are unmet. I move onto the next patient. I feel good, but in actuality, I didn’t hear her. I have provided her bias and stereotyped care. I missed an opportunity to truly engage this patient and her care, and my good intentions of following the literature about her experience in menopause have contributed quite likely to her increased morbidity and mortality, her increased cardiovascular disease risk, all because I have not held space for her cultural identity.

References

1. Harlow SD, Burnett-Bowie SM, Greendale GA, et al. Disparities in reproductive aging and midlife health between Black and White women: the Study of Women’s Health Across the Nation (SWAN). Women’s Midlife Health. 2022;8:3. doi: 10.1186/s40695-022-00073-y.
2. Chlebowski RT, Aragaki AK, Anderson GL, et al. Forty-year trends in menopausal hormone therapy use and breast cancer incidence among postmenopausal black and white women. Cancer. 2020;126:2956-2964. doi: 10.1002/ cncr.32846.
3. Weng HH, McBride CM, Bosworth HB, et al. Racial differences in physician recommendation of hormone replacement therapy. Prev Med. 2001;33:668673. doi: 10.1006/pmed.2001.0943.
4. Williams M, Richard-Davis G, Williams PL, et al. A review of African American women’s experiences in menopause. Menopause. 2022;29:1331-1337. doi: 10.1097/GME.0000000000002060.
5. Im EO. Ethnic differences in symptoms experienced during the menopausal transition. Health Care Women Int. 2009;30:339-355. doi: 10.1080/07399330802695002.

OBG Management caught up with Drs. Jan Shifren and Genevieve Neal-Perry while they were attending the annual meeting of The North American Menopause Society (NAMS), held October 12-15, 2022, in Atlanta, Georgia. Dr. Shifren presented on the “Ins and Outs of Hormone Therapy,” while Dr. Neal-Perry focused on “Menopause Physiology.” 

Evaluating symptomatic patients for appropriate hormone therapy

OBG Management: In your presentation to the group at the NAMS meeting, you described a 51-year-old patient with the principal symptoms of frequent hot flashes and night sweats, sleep disruption, fatigue, irritability, vaginal dryness, and dyspareunia. As she reported already trying several lifestyle modification approaches, what are your questions for her to determine whether hormone therapy (HT), systemic or low-dose vaginal, is advisable?

Jan Shifren, MD: As with every patient, you need to begin with a thorough history and confirm her physical exam is up to date. If there are concerns related to genitourinary symptoms of menopause (GSM), then a pelvic exam is indicated. This patient is a healthy menopausal woman with bothersome hot flashes, night sweats, and vaginal dryness. Sleep disruption from night sweats is likely the cause of her fatigue and irritability, and her dyspareunia due to atrophic vulvovaginal changes. The principal indication for systemic HT is bothersome vasomotor symptoms (VMS), and a healthy woman who is under age 60 or within 10 years of the onset of menopause is generally a very good candidate for hormones. For this healthy 51-year-old with bothersome VMS unresponsive to lifestyle modification, the benefits of HT should outweigh potential risks. As low-dose vaginal estrogen therapy is minimally absorbed and very safe, this would be recommended instead of systemic HT if her only menopause symptoms were vaginal dryness and dyspareunia.

HT types and formulations

OBG Management: For this patient, low-dose vaginal estrogen is appropriate. In general, how do you decide on recommendations for combination therapy or estrogen only, and what formulations and dosages do you recommend?

Dr. Shifren: Any woman with a uterus needs to take a progestogen together with estrogen to protect her uterus from estrogen-induced endometrial overgrowth. With low dose vaginal estrogen therapy, however, concurrent progestogen is not needed.

Continue to: Estrogen options...

Many of our patients like the idea that they are using “natural” HT. I inform them that bioidentical is a marketing term rather than a medical term, but if their goal is to take the same hormones that their ovaries made when they were younger, they should use FDA-approved formulations of estradiol and progesterone for their menopausal HT symptoms. I do not recommend compounded bioidentical HT due to concerns regarding product quality and safety. The combination of FDA-approved estradiol patches and oral micronized progesterone provides a high quality, carefully regulated bioidentical HT regimen. For women greatly preferring an oral estrogen, oral estradiol with micronized progesterone is an option.

In addition to patient preference for natural HT, the reasons that I encourage women to consider the estradiol transdermal patch for their menopausal HT include:

1. no increased risk of venous thromboembolic events when physiologically dosed menopausal estradiol therapy is provided by a skin patch (observational data).¹ With oral estrogens, even when dosed for menopause, VTE risk increases, as coagulation factors increase due to the first-pass hepatic effect. This does not occur with non-oral menopausal estrogens.
2. no increased risk of gallbladder disease, which occurs with oral estrogen therapy (observational data)²
3. possibly lower risk of stroke when low-dose menopausal HT is provided via skin patch (observational data)³
4. convenience—the patches are changed once or twice weekly
5. wide range of doses available, which optimizes identifying the lowest effective dose and decreasing the dose over time.

Progestogen options. Progestogens may be given daily or cyclically. Use of daily progestogen typically results in amenorrhea, which is preferred by most women. Cyclic use of a progestogen for 12-14 days each month results in a monthly withdrawal bleed, which is a good option for a woman experiencing bothersome breakthrough bleeding with daily progestogen. Use of a progestogen-releasing IUD is an off-label alternative for endometrial protection with menopausal HT. As discussed earlier, as many women prefer bioidentical HT, one of our preferred regimens is to provide transdermal estradiol with FDA-approved oral micronized progesterone. There are several patches that combine estradiol with a progestogen, but there is not a lot of dosing flexibility and product choice. There also is an approved product available that combines oral estradiol and micronized progesterone in one tablet.

Scheduling follow-up

OBG Management: Now that you have started the opening case patient on HT, how often are you going to monitor her for treatment?

Dr. Shifren: Women will not experience maximum efficacy for hot flash relief from their estrogen therapy for 3 months, so I typically see a patient back at 3 to 4 months to assess side effects and symptom control. I encourage women to reach out sooner if they are having a bothersome side effect. Once she is doing well on an HT regimen, we assess risks and benefits of ongoing treatment annually. The goal is to be certain she is on the lowest dose of estrogen that treats her symptoms, and we slowly decrease the estrogen dose over time.

Breast cancer risk

OBG Management: In your presentation, you mentioned that the risk of breast cancer does not increase appreciably with short-term use of HT. Is it possible to define short term?

Dr. Shifren: In the Women’s Health Initiative (WHI), a large double-blind, randomized, placebo-controlled trial of menopausal HT, there was a slight increase in breast cancer risk after approximately 4 to 5 years of use in women using estrogen with progestogen.⁴ I share with patients that this increased risk is about the same as that of obesity or drinking more than 1 alcoholic beverage daily. As an increased risk of breast cancer does not occur for several years, a woman may be able to take hormones for bothersome symptoms, feel well, and slowly come off without incurring significant breast cancer risk. In the WHI, there was no increase in breast cancer risk in women without a uterus randomized to estrogen alone.

Regarding cardiovascular risk, in the WHI, an increased risk of cardiovascular events generally was not seen in healthy women younger than age 60 and within 10 years of the onset of menopause.⁵ Benefits of HT may not outweigh risks for women with significant underlying cardiovascular risk factors, even if they are younger and close to menopause onset.

Continue to: The importance of shared decision making...

 

 

The importance of shared decision making

Dr. Shifren: As with any important health care decision, women should be involved in an individualized discussion of risks and benefits, with shared decision making about whether HT is the right choice. Women also should be involved in ongoing decisions regarding HT formulation, dose, and duration of use.

A nonhormonal option for hot flashes

OBG Management: How many women experience VMS around the time of menopause?

Dr. Genevieve Neal-Perry, MD, PhD: About 60% to 70% of individuals will experience hot flashes around the time of the menopause.⁶ Of those, about 40% are what we would call moderate to severe hot flashes—which are typically the most disruptive in terms of quality of life.⁷ The window of time in which they are likely to have them, at typically their most intense timeframe, is 2 years before the final menstrual period and the year after.⁷ In terms of the average duration, however, it’s about 7 years, which is a lot longer than what we previously thought.⁸ Moreover, there are disparities in that women of color, particularly African American women, can have them as long as 10 years.⁸
 

OBG Management: Can you explain why the VMS occur, and specifically around the time of menopause?

Dr. Neal-Perry: For many years we did not understand the basic biology of hot flashes. When you think about it, it’s completely amazing—when half of our population experiences hot flashes, and we don’t understand why, and we don’t have therapy that specifically targets hot flashes.

What we now know from work completed by Naomi Rance, in particular, is that a specific region of the brain, the hypothalamus, exhibited changes in number of neurons that seemed to be increased in size in menopausal people and smaller in size in people who were not menopausal.⁹ That started the journey to understanding the biology, and eventual mechanism, of hot flashes. It took about 10-15 years before we really began to understand why.

What we know now is that estrogen, a hormone that is made by the ovaries, activates and inactivates neurons located in the hypothalamus, a brain region that controls our thermoregulation—the way your body perceives temperature. The hypothalamus controls your response to temperature, either you experience chills or you dissipate heat by vasodilating (hot flush) and sweating.

The thermoregulatory region of the hypothalamus houses cells that receive messages from KNDy neurons, neurons also located in the hypothalamus that express kisspeptin, neurokinin, and dynorphin. Importantly, KNDy neurons express estrogen receptors. (The way that I like to think about estrogen and estrogen receptors is that estrogen is like the ball and the receptor is like the catcher’s mitt.) When estrogen interacts with this receptor, it keeps KNDy neurons quiet. But the increased variability and loss of estrogen that occurs around the time of menopause “disinhibits” KNDy neurons—meaning that they are no longer being reined in by estrogen. In response to decreased estrogen regulation, KNDy neurons become hypertrophied with neurotransmitters and more active. Specifically, KNDy neurons release neurokinin, a neuropeptide that self-stimulates KNDy neurons and activates neurons in the thermoregulatory zone of the brain—it’s a speed-forward feed-backward mechanism. The thermoregulatory neurons interpret this signal as “I feel hot,” and the body begins a series of functions to cool things down.

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Continue to: Treatments that act on the thermoregulatory region

 

 

Treatments that act on the thermoregulatory region

Dr. Neal-Perry: I have described what happens in the brain around the time of menopause, and what triggers those hot flashes.

Estrogen. The reason that estrogen worked to treat the hot flashes is because estrogen inhibits and calms the neurons that become hyperactive during the menopause.

Fezolinetant. Fezolinetant is unique because it specifically targets the hormone receptor that triggers hot flashes, the neurokinin receptor. Fezolinetant is a nonhormone therapy that not only reduces the activity of KNDy neurons but also blocks the effects of neurons in the thermoregulatory zone, thereby reducing the sensation of the hot flashes. We are in such a special time in medical history for individuals who experience hot flashes because now we understand the basic biology of hot flashes, and we can generate targeted therapy to manage hot flashes—that is for both individuals who identify as women and individuals who identify as men, because both experience hot flashes.
 

OBG Management: Is there a particular threshold of hot flash symptoms that is considered important to treat, or is treatment based on essentially the bother to patients?

Dr. Neal-Perry: Treatment is solely based on if it bothers the patient. But we do know that people who have lots of bothersome hot flashes have a higher risk for heart disease and may have sleep disruption, reduced cognitive function, and poorer quality of life. Sleep dysfunction can impact the ability to think and function and can put those affected at increased risk for accidents.

For people who are having these symptoms that are disruptive to their life, you do want to treat them. You might say, “Well, we’ve had estrogen, why not use estrogen,” right? Well estrogen works very well, but there are lots of people who can’t use estrogen—individuals who have breast cancer, blood clotting disorders, significant heart disease, or diabetes. Then there are just some people who don’t feel comfortable using estrogen.

We have had a huge gap in care for individuals who experience hot flashes and who are ineligible for menopausal HT. While there are other nonhormonal options, they often have side effects like sexual dysfunction, hypersomnolence, or insomnia. Some people choose not to use these nonhormonal treatments because the side effects are worse for them than to trying to manage the hot flashes. The introduction to a nonhormonal therapy that is effective and does not have lots of side effects is exciting and will be welcomed by many who have not found relief.
 

OBG Management: Is fezolinetant available now for patients?

Dr. Neal-Perry: It is not available yet. Hopefully, it will be approved within the next year. Astellas recently completed a double blind randomized cross over design phase 3 study that found fezolinetant is highly effective for the management of hot flashes and that it has a low side effect profile.¹⁰ Fezolinetant’s most common side effect was COVID-19, a reflection of the fact that the trial was done during the COVID pandemic. The other most common side effect was headache. Everything else was minimal.

Other drugs in the same class as fezolinetant have been under development for the management of hot flashes; however, they encountered liver function challenges, and studies were stopped. Fezolinetant did not cause liver dysfunction.

Hot flash modifiers

OBG Management: Referring to that neuropathway, are there physiologic differences among women who do and do not experience hot flashes, and are there particular mechanisms that may protect patients against being bothered by hot flashes?

Dr. Neal-Perry: Well, there are some things that we can control, and there are things that we cannot control (like our genetic background). Some of the processes that are important for estrogen receptor function and estrogen metabolism, as well as some other receptor systems, can work differently. When estrogen metabolism is slightly different, it could result in reduced estrogen receptor activity and more hot flashes. Then there are some receptor polymorphisms that can increase or reduce the risk for hot flashes—the genetic piece.¹¹

There are things that can modify your risk for hot flashes and the duration of hot flashes. Individuals who are obese or smoke may experience more hot flashes. Women of color, especially African American women, tend to have hot flashes occur earlier in their reproductive life and last for a longer duration; hot flashes may occur up to 2 years before menopause, last for more than 10 years, and be more disruptive. By contrast, Asian women tend to report fewer and less disruptive hot flashes.⁸
 

OBG Management: If fezolinetant were to be FDA approved, will there be particular patients that it will most appropriate for, since it is an estrogen alternative?

Dr. Neal-Perry: Yes, there may be different patients who might benefit from fezolinetant. This will depend on what the situation is—patients who have breast cancer, poorly controlled diabetes, or heart disease, and those patients who prefer not to use estrogen will benefit from fezolinetant, as we are going to look for other treatment options for those individuals. It will be important for medical providers to listen to their patients and understand the medical background of that individual to really define what is the best next step for the management of their hot flashes.

This is an exciting time for individuals affected by menopausal hot flashes; to understand the biology of hot flashes gives us real opportunities to bridge gaps around how to manage them. Individuals who experience hot flashes will know that they don’t have to suffer, that there are other options that are safe, that can help meet their needs and put them in a better place. ●

Multiethnic differences in the menopause experience

---

Excerpted from the presentation, “Do you see me? Culturally responsive care in menopause,” by Makeba Williams, MD, NCMP, at The North American Menopause Society meeting in Atlanta, Georgia, October 12-15, 2022.

Dr. Williams is Vice Chair of Professional Development and Wellness, Associate Professor, Washington University School of Medicine

The Study of Women’s Health Across the Nation (SWAN) challenged the notion that there is a universal menopausal experience.¹ Up until that time, we had been using this universal experience that is based largely on the experiences of White women and applying that data to the experiences of women of color. Other research has shown that African American women have poorer quality of life and health status, and that they receive less treatment for a number of conditions.^2,3

In a recent review of more than 20 years of literature, we found only 17 articles that met the inclusion criteria, reflecting the invisibility of African American women and other ethnic and racial minorities in the menopause literature and research. Key findings included that African American women^1,4:

• experience an earlier age of onset of menopause
• have higher rates of premature menopause and early menopause, which is a risk factor for cardiovascular disease
• experience a longer time of the menopausal transition, with variability in the average age of menopause onset
• overall report lower rates of vaginal symptoms
• are less likely to report sleep disturbances than White women or Hispanic women, but more likely to report these symptoms than Asian women
• experience a higher prevalence, frequency, and severity of vasomotor symptoms (VMS), and were more bothered by those symptoms

− 48.4 years in the Healthy Women’s Study

− 50.9 years in the Penn Ovarian Aging Study

− 51.4 years in SWAN

• reported lower educational attainment, experiencing more socioeconomic disadvantage and exposure to more adverse life effects
• receive less treatment for VMS, hypertension, and depression, and are less likely to be prescribed statin drugs
• experience more discrimination
• use cigarettes and tobacco more, but are less likely to use alcohol and less likely to have physical activity.

Cultural influences on menopause

Im and colleagues have published many studies looking at cultural influences on African American, Hispanic, and Asian American women, and comparing them to White women.⁵ Notable differences were found regarding education level, family income, employment, number of children, and greater perceived health (which is associated with fewer menopausal symptoms). They identified 5 qualitative ideas:

1. Positive acceptance. Minority women, or racial and ethnic women, perceived the transition to menopause more positively, and generally took on a posture of acceptance, reporting feeling liberated from many of the challenges associated with the reproductive period. In addition, many associated a greater sense of maturity and respect within their communities with the natural aging process.
2. Optimism. Ethnic women tended to embrace menopause, using humor and laughter to express emotions during stressful life changes. This runs counter to many of the perspectives reported by White women, who often viewed the menopausal transition and aging negatively, as we equate aging with the loss of youthfulness in the United States.
3. Unique, not universal. Most of the ethnic minority women thought that there was something unique about their menopausal experiences, and that they were influenced by immigration transition, financial situations, etc. Many White woman perceived that the menopausal experience was shared among all women.
4. Closed, not open. There were differences in how we talk about symptoms, or whether or not we talk about them at all. Ethnic women tended to be silent about their symptoms. By contrast, White women tended to be more open and talkative and communicative about their symptoms.
5. Minimizing, not controlling. No symptom management was the strategy of choice for most women. Minority women tended to manage their symptoms by tolerating and normalizing them. Only those women with the most serious symptoms sought out medication for temporary relief. Some expressed a tendency to downplay their symptoms because many of them had more important things that they were dealing with in their lives.

What is an individual social identity?

An individual social identity reflects the many groups to which one belongs. It is how one shows up, and yet it is much more than how they physically show up. When you pass your eye on patients, you are only seeing the tip of the iceberg. The full social identity of a patient resides below the surface. Social identity is complex, on a continuum, and can change depending on time and place. How we prioritize our social identities may change, depending on the context and the situation.

Our intersecting social identities give rise to our cultural identity, and it is through the prism of intersectionality that we can understand the ways in which our social identities converge to give rise to disparities in health care in midlife and menopausal women. Holding space for cultural identity, we can impact how our patients are perceiving their menopause, how they are moving through decision making about taking care of themselves in menopause. And we can provide more responsive care to their cultural identities, and hopefully at the end of the day we reduce some of these disparities that we are seeing in our menopausal patients and also are reducing our unconscious bias in our patient interactions.

Culturally responsive care

There are several components to home in on when we are trying to provide culturally responsive care to patients.

1. A commitment to being culturally curious. We have to accept what the literature is sharing with us, that there is not a universal menopausal experience. We have for far too long applied this universal experience of menopause that has largely been based on White women to different racial and ethnic populations.
2. Recognizing. I appreciate that my identity as a Black woman may be very different from other Black women in the room, or whatever their social identity. I am not expected to understand all of the others’ experiences, and I don’t expect that for you either.
3. Acknowledge unconscious implicit biases. Acknowledge the groups to which you have a strong implicit bias, and allow it to drive you to reduce barriers to engaging with patients.
4. Connecting with the individual patient. It is through a process of individuating that we learn from our patients’ unique characteristics, rather than relying on assumptions and stereotypes. We have a window of opportunity to see our patient and move beyond thinking of them in terms of racial and ethnic stereotypes or particular social groups. It is through this process of individualizing that we can seek answers to key questions.

The ultimate goal is to understand our individual patients’ perceptions, outlook on menopause, and contextual factors in their lives that influence the menopause journey.

CASE ENCOUNTER

I quickly look at the patient-filled form before I knock on the exam door, and I see that the patient has checked off that she has hot flashes, night sweats, and I make a mental note, she’s menopausal. I already have a preliminary plan to give this patient hormone therapy. I open the door, and I see that she’s Black. I know, based upon the data from SWAN and others, that her menopause means longer duration, more severe vasomotor symptoms. I have already teed up a prescription to go to the pharmacy.

The problem is, I have not even talked to her. She may actually nod her head, saying that she is going to go to the pharmacy, but she may never pick up that prescription. She likely leaves my office feeling unheard; her needs are unmet. I move onto the next patient. I feel good, but in actuality, I didn’t hear her. I have provided her bias and stereotyped care. I missed an opportunity to truly engage this patient and her care, and my good intentions of following the literature about her experience in menopause have contributed quite likely to her increased morbidity and mortality, her increased cardiovascular disease risk, all because I have not held space for her cultural identity.

References

1. Harlow SD, Burnett-Bowie SM, Greendale GA, et al. Disparities in reproductive aging and midlife health between Black and White women: the Study of Women’s Health Across the Nation (SWAN). Women’s Midlife Health. 2022;8:3. doi: 10.1186/s40695-022-00073-y.
2. Chlebowski RT, Aragaki AK, Anderson GL, et al. Forty-year trends in menopausal hormone therapy use and breast cancer incidence among postmenopausal black and white women. Cancer. 2020;126:2956-2964. doi: 10.1002/ cncr.32846.
3. Weng HH, McBride CM, Bosworth HB, et al. Racial differences in physician recommendation of hormone replacement therapy. Prev Med. 2001;33:668673. doi: 10.1006/pmed.2001.0943.
4. Williams M, Richard-Davis G, Williams PL, et al. A review of African American women’s experiences in menopause. Menopause. 2022;29:1331-1337. doi: 10.1097/GME.0000000000002060.
5. Im EO. Ethnic differences in symptoms experienced during the menopausal transition. Health Care Women Int. 2009;30:339-355. doi: 10.1080/07399330802695002.

OBG Management caught up with Drs. Jan Shifren and Genevieve Neal-Perry while they were attending the annual meeting of The North American Menopause Society (NAMS), held October 12-15, 2022, in Atlanta, Georgia. Dr. Shifren presented on the “Ins and Outs of Hormone Therapy,” while Dr. Neal-Perry focused on “Menopause Physiology.” 

Evaluating symptomatic patients for appropriate hormone therapy

OBG Management: In your presentation to the group at the NAMS meeting, you described a 51-year-old patient with the principal symptoms of frequent hot flashes and night sweats, sleep disruption, fatigue, irritability, vaginal dryness, and dyspareunia. As she reported already trying several lifestyle modification approaches, what are your questions for her to determine whether hormone therapy (HT), systemic or low-dose vaginal, is advisable?

Jan Shifren, MD: As with every patient, you need to begin with a thorough history and confirm her physical exam is up to date. If there are concerns related to genitourinary symptoms of menopause (GSM), then a pelvic exam is indicated. This patient is a healthy menopausal woman with bothersome hot flashes, night sweats, and vaginal dryness. Sleep disruption from night sweats is likely the cause of her fatigue and irritability, and her dyspareunia due to atrophic vulvovaginal changes. The principal indication for systemic HT is bothersome vasomotor symptoms (VMS), and a healthy woman who is under age 60 or within 10 years of the onset of menopause is generally a very good candidate for hormones. For this healthy 51-year-old with bothersome VMS unresponsive to lifestyle modification, the benefits of HT should outweigh potential risks. As low-dose vaginal estrogen therapy is minimally absorbed and very safe, this would be recommended instead of systemic HT if her only menopause symptoms were vaginal dryness and dyspareunia.

HT types and formulations

OBG Management: For this patient, low-dose vaginal estrogen is appropriate. In general, how do you decide on recommendations for combination therapy or estrogen only, and what formulations and dosages do you recommend?

Dr. Shifren: Any woman with a uterus needs to take a progestogen together with estrogen to protect her uterus from estrogen-induced endometrial overgrowth. With low dose vaginal estrogen therapy, however, concurrent progestogen is not needed.

Continue to: Estrogen options...

Many of our patients like the idea that they are using “natural” HT. I inform them that bioidentical is a marketing term rather than a medical term, but if their goal is to take the same hormones that their ovaries made when they were younger, they should use FDA-approved formulations of estradiol and progesterone for their menopausal HT symptoms. I do not recommend compounded bioidentical HT due to concerns regarding product quality and safety. The combination of FDA-approved estradiol patches and oral micronized progesterone provides a high quality, carefully regulated bioidentical HT regimen. For women greatly preferring an oral estrogen, oral estradiol with micronized progesterone is an option.

In addition to patient preference for natural HT, the reasons that I encourage women to consider the estradiol transdermal patch for their menopausal HT include:

1. no increased risk of venous thromboembolic events when physiologically dosed menopausal estradiol therapy is provided by a skin patch (observational data).¹ With oral estrogens, even when dosed for menopause, VTE risk increases, as coagulation factors increase due to the first-pass hepatic effect. This does not occur with non-oral menopausal estrogens.
2. no increased risk of gallbladder disease, which occurs with oral estrogen therapy (observational data)²
3. possibly lower risk of stroke when low-dose menopausal HT is provided via skin patch (observational data)³
4. convenience—the patches are changed once or twice weekly
5. wide range of doses available, which optimizes identifying the lowest effective dose and decreasing the dose over time.

Progestogen options. Progestogens may be given daily or cyclically. Use of daily progestogen typically results in amenorrhea, which is preferred by most women. Cyclic use of a progestogen for 12-14 days each month results in a monthly withdrawal bleed, which is a good option for a woman experiencing bothersome breakthrough bleeding with daily progestogen. Use of a progestogen-releasing IUD is an off-label alternative for endometrial protection with menopausal HT. As discussed earlier, as many women prefer bioidentical HT, one of our preferred regimens is to provide transdermal estradiol with FDA-approved oral micronized progesterone. There are several patches that combine estradiol with a progestogen, but there is not a lot of dosing flexibility and product choice. There also is an approved product available that combines oral estradiol and micronized progesterone in one tablet.

Scheduling follow-up

OBG Management: Now that you have started the opening case patient on HT, how often are you going to monitor her for treatment?

Dr. Shifren: Women will not experience maximum efficacy for hot flash relief from their estrogen therapy for 3 months, so I typically see a patient back at 3 to 4 months to assess side effects and symptom control. I encourage women to reach out sooner if they are having a bothersome side effect. Once she is doing well on an HT regimen, we assess risks and benefits of ongoing treatment annually. The goal is to be certain she is on the lowest dose of estrogen that treats her symptoms, and we slowly decrease the estrogen dose over time.

Breast cancer risk

OBG Management: In your presentation, you mentioned that the risk of breast cancer does not increase appreciably with short-term use of HT. Is it possible to define short term?

Dr. Shifren: In the Women’s Health Initiative (WHI), a large double-blind, randomized, placebo-controlled trial of menopausal HT, there was a slight increase in breast cancer risk after approximately 4 to 5 years of use in women using estrogen with progestogen.⁴ I share with patients that this increased risk is about the same as that of obesity or drinking more than 1 alcoholic beverage daily. As an increased risk of breast cancer does not occur for several years, a woman may be able to take hormones for bothersome symptoms, feel well, and slowly come off without incurring significant breast cancer risk. In the WHI, there was no increase in breast cancer risk in women without a uterus randomized to estrogen alone.

Regarding cardiovascular risk, in the WHI, an increased risk of cardiovascular events generally was not seen in healthy women younger than age 60 and within 10 years of the onset of menopause.⁵ Benefits of HT may not outweigh risks for women with significant underlying cardiovascular risk factors, even if they are younger and close to menopause onset.

Continue to: The importance of shared decision making...

 

 

The importance of shared decision making

Dr. Shifren: As with any important health care decision, women should be involved in an individualized discussion of risks and benefits, with shared decision making about whether HT is the right choice. Women also should be involved in ongoing decisions regarding HT formulation, dose, and duration of use.

A nonhormonal option for hot flashes

OBG Management: How many women experience VMS around the time of menopause?

Dr. Genevieve Neal-Perry, MD, PhD: About 60% to 70% of individuals will experience hot flashes around the time of the menopause.⁶ Of those, about 40% are what we would call moderate to severe hot flashes—which are typically the most disruptive in terms of quality of life.⁷ The window of time in which they are likely to have them, at typically their most intense timeframe, is 2 years before the final menstrual period and the year after.⁷ In terms of the average duration, however, it’s about 7 years, which is a lot longer than what we previously thought.⁸ Moreover, there are disparities in that women of color, particularly African American women, can have them as long as 10 years.⁸
 

OBG Management: Can you explain why the VMS occur, and specifically around the time of menopause?

Dr. Neal-Perry: For many years we did not understand the basic biology of hot flashes. When you think about it, it’s completely amazing—when half of our population experiences hot flashes, and we don’t understand why, and we don’t have therapy that specifically targets hot flashes.

What we now know from work completed by Naomi Rance, in particular, is that a specific region of the brain, the hypothalamus, exhibited changes in number of neurons that seemed to be increased in size in menopausal people and smaller in size in people who were not menopausal.⁹ That started the journey to understanding the biology, and eventual mechanism, of hot flashes. It took about 10-15 years before we really began to understand why.

What we know now is that estrogen, a hormone that is made by the ovaries, activates and inactivates neurons located in the hypothalamus, a brain region that controls our thermoregulation—the way your body perceives temperature. The hypothalamus controls your response to temperature, either you experience chills or you dissipate heat by vasodilating (hot flush) and sweating.

The thermoregulatory region of the hypothalamus houses cells that receive messages from KNDy neurons, neurons also located in the hypothalamus that express kisspeptin, neurokinin, and dynorphin. Importantly, KNDy neurons express estrogen receptors. (The way that I like to think about estrogen and estrogen receptors is that estrogen is like the ball and the receptor is like the catcher’s mitt.) When estrogen interacts with this receptor, it keeps KNDy neurons quiet. But the increased variability and loss of estrogen that occurs around the time of menopause “disinhibits” KNDy neurons—meaning that they are no longer being reined in by estrogen. In response to decreased estrogen regulation, KNDy neurons become hypertrophied with neurotransmitters and more active. Specifically, KNDy neurons release neurokinin, a neuropeptide that self-stimulates KNDy neurons and activates neurons in the thermoregulatory zone of the brain—it’s a speed-forward feed-backward mechanism. The thermoregulatory neurons interpret this signal as “I feel hot,” and the body begins a series of functions to cool things down.

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Continue to: Treatments that act on the thermoregulatory region

 

 

Treatments that act on the thermoregulatory region

Dr. Neal-Perry: I have described what happens in the brain around the time of menopause, and what triggers those hot flashes.

Estrogen. The reason that estrogen worked to treat the hot flashes is because estrogen inhibits and calms the neurons that become hyperactive during the menopause.

Fezolinetant. Fezolinetant is unique because it specifically targets the hormone receptor that triggers hot flashes, the neurokinin receptor. Fezolinetant is a nonhormone therapy that not only reduces the activity of KNDy neurons but also blocks the effects of neurons in the thermoregulatory zone, thereby reducing the sensation of the hot flashes. We are in such a special time in medical history for individuals who experience hot flashes because now we understand the basic biology of hot flashes, and we can generate targeted therapy to manage hot flashes—that is for both individuals who identify as women and individuals who identify as men, because both experience hot flashes.
 

OBG Management: Is there a particular threshold of hot flash symptoms that is considered important to treat, or is treatment based on essentially the bother to patients?

Dr. Neal-Perry: Treatment is solely based on if it bothers the patient. But we do know that people who have lots of bothersome hot flashes have a higher risk for heart disease and may have sleep disruption, reduced cognitive function, and poorer quality of life. Sleep dysfunction can impact the ability to think and function and can put those affected at increased risk for accidents.

For people who are having these symptoms that are disruptive to their life, you do want to treat them. You might say, “Well, we’ve had estrogen, why not use estrogen,” right? Well estrogen works very well, but there are lots of people who can’t use estrogen—individuals who have breast cancer, blood clotting disorders, significant heart disease, or diabetes. Then there are just some people who don’t feel comfortable using estrogen.

We have had a huge gap in care for individuals who experience hot flashes and who are ineligible for menopausal HT. While there are other nonhormonal options, they often have side effects like sexual dysfunction, hypersomnolence, or insomnia. Some people choose not to use these nonhormonal treatments because the side effects are worse for them than to trying to manage the hot flashes. The introduction to a nonhormonal therapy that is effective and does not have lots of side effects is exciting and will be welcomed by many who have not found relief.
 

OBG Management: Is fezolinetant available now for patients?

Dr. Neal-Perry: It is not available yet. Hopefully, it will be approved within the next year. Astellas recently completed a double blind randomized cross over design phase 3 study that found fezolinetant is highly effective for the management of hot flashes and that it has a low side effect profile.¹⁰ Fezolinetant’s most common side effect was COVID-19, a reflection of the fact that the trial was done during the COVID pandemic. The other most common side effect was headache. Everything else was minimal.

Other drugs in the same class as fezolinetant have been under development for the management of hot flashes; however, they encountered liver function challenges, and studies were stopped. Fezolinetant did not cause liver dysfunction.

Hot flash modifiers

OBG Management: Referring to that neuropathway, are there physiologic differences among women who do and do not experience hot flashes, and are there particular mechanisms that may protect patients against being bothered by hot flashes?

Dr. Neal-Perry: Well, there are some things that we can control, and there are things that we cannot control (like our genetic background). Some of the processes that are important for estrogen receptor function and estrogen metabolism, as well as some other receptor systems, can work differently. When estrogen metabolism is slightly different, it could result in reduced estrogen receptor activity and more hot flashes. Then there are some receptor polymorphisms that can increase or reduce the risk for hot flashes—the genetic piece.¹¹

There are things that can modify your risk for hot flashes and the duration of hot flashes. Individuals who are obese or smoke may experience more hot flashes. Women of color, especially African American women, tend to have hot flashes occur earlier in their reproductive life and last for a longer duration; hot flashes may occur up to 2 years before menopause, last for more than 10 years, and be more disruptive. By contrast, Asian women tend to report fewer and less disruptive hot flashes.⁸
 

OBG Management: If fezolinetant were to be FDA approved, will there be particular patients that it will most appropriate for, since it is an estrogen alternative?

Dr. Neal-Perry: Yes, there may be different patients who might benefit from fezolinetant. This will depend on what the situation is—patients who have breast cancer, poorly controlled diabetes, or heart disease, and those patients who prefer not to use estrogen will benefit from fezolinetant, as we are going to look for other treatment options for those individuals. It will be important for medical providers to listen to their patients and understand the medical background of that individual to really define what is the best next step for the management of their hot flashes.

This is an exciting time for individuals affected by menopausal hot flashes; to understand the biology of hot flashes gives us real opportunities to bridge gaps around how to manage them. Individuals who experience hot flashes will know that they don’t have to suffer, that there are other options that are safe, that can help meet their needs and put them in a better place. ●

Multiethnic differences in the menopause experience

---

Excerpted from the presentation, “Do you see me? Culturally responsive care in menopause,” by Makeba Williams, MD, NCMP, at The North American Menopause Society meeting in Atlanta, Georgia, October 12-15, 2022.

Dr. Williams is Vice Chair of Professional Development and Wellness, Associate Professor, Washington University School of Medicine

The Study of Women’s Health Across the Nation (SWAN) challenged the notion that there is a universal menopausal experience.¹ Up until that time, we had been using this universal experience that is based largely on the experiences of White women and applying that data to the experiences of women of color. Other research has shown that African American women have poorer quality of life and health status, and that they receive less treatment for a number of conditions.^2,3

In a recent review of more than 20 years of literature, we found only 17 articles that met the inclusion criteria, reflecting the invisibility of African American women and other ethnic and racial minorities in the menopause literature and research. Key findings included that African American women^1,4:

• experience an earlier age of onset of menopause
• have higher rates of premature menopause and early menopause, which is a risk factor for cardiovascular disease
• experience a longer time of the menopausal transition, with variability in the average age of menopause onset
• overall report lower rates of vaginal symptoms
• are less likely to report sleep disturbances than White women or Hispanic women, but more likely to report these symptoms than Asian women
• experience a higher prevalence, frequency, and severity of vasomotor symptoms (VMS), and were more bothered by those symptoms

− 48.4 years in the Healthy Women’s Study

− 50.9 years in the Penn Ovarian Aging Study

− 51.4 years in SWAN

• reported lower educational attainment, experiencing more socioeconomic disadvantage and exposure to more adverse life effects
• receive less treatment for VMS, hypertension, and depression, and are less likely to be prescribed statin drugs
• experience more discrimination
• use cigarettes and tobacco more, but are less likely to use alcohol and less likely to have physical activity.

Cultural influences on menopause

Im and colleagues have published many studies looking at cultural influences on African American, Hispanic, and Asian American women, and comparing them to White women.⁵ Notable differences were found regarding education level, family income, employment, number of children, and greater perceived health (which is associated with fewer menopausal symptoms). They identified 5 qualitative ideas:

1. Positive acceptance. Minority women, or racial and ethnic women, perceived the transition to menopause more positively, and generally took on a posture of acceptance, reporting feeling liberated from many of the challenges associated with the reproductive period. In addition, many associated a greater sense of maturity and respect within their communities with the natural aging process.
2. Optimism. Ethnic women tended to embrace menopause, using humor and laughter to express emotions during stressful life changes. This runs counter to many of the perspectives reported by White women, who often viewed the menopausal transition and aging negatively, as we equate aging with the loss of youthfulness in the United States.
3. Unique, not universal. Most of the ethnic minority women thought that there was something unique about their menopausal experiences, and that they were influenced by immigration transition, financial situations, etc. Many White woman perceived that the menopausal experience was shared among all women.
4. Closed, not open. There were differences in how we talk about symptoms, or whether or not we talk about them at all. Ethnic women tended to be silent about their symptoms. By contrast, White women tended to be more open and talkative and communicative about their symptoms.
5. Minimizing, not controlling. No symptom management was the strategy of choice for most women. Minority women tended to manage their symptoms by tolerating and normalizing them. Only those women with the most serious symptoms sought out medication for temporary relief. Some expressed a tendency to downplay their symptoms because many of them had more important things that they were dealing with in their lives.

What is an individual social identity?

An individual social identity reflects the many groups to which one belongs. It is how one shows up, and yet it is much more than how they physically show up. When you pass your eye on patients, you are only seeing the tip of the iceberg. The full social identity of a patient resides below the surface. Social identity is complex, on a continuum, and can change depending on time and place. How we prioritize our social identities may change, depending on the context and the situation.

Our intersecting social identities give rise to our cultural identity, and it is through the prism of intersectionality that we can understand the ways in which our social identities converge to give rise to disparities in health care in midlife and menopausal women. Holding space for cultural identity, we can impact how our patients are perceiving their menopause, how they are moving through decision making about taking care of themselves in menopause. And we can provide more responsive care to their cultural identities, and hopefully at the end of the day we reduce some of these disparities that we are seeing in our menopausal patients and also are reducing our unconscious bias in our patient interactions.

Culturally responsive care

There are several components to home in on when we are trying to provide culturally responsive care to patients.

1. A commitment to being culturally curious. We have to accept what the literature is sharing with us, that there is not a universal menopausal experience. We have for far too long applied this universal experience of menopause that has largely been based on White women to different racial and ethnic populations.
2. Recognizing. I appreciate that my identity as a Black woman may be very different from other Black women in the room, or whatever their social identity. I am not expected to understand all of the others’ experiences, and I don’t expect that for you either.
3. Acknowledge unconscious implicit biases. Acknowledge the groups to which you have a strong implicit bias, and allow it to drive you to reduce barriers to engaging with patients.
4. Connecting with the individual patient. It is through a process of individuating that we learn from our patients’ unique characteristics, rather than relying on assumptions and stereotypes. We have a window of opportunity to see our patient and move beyond thinking of them in terms of racial and ethnic stereotypes or particular social groups. It is through this process of individualizing that we can seek answers to key questions.

The ultimate goal is to understand our individual patients’ perceptions, outlook on menopause, and contextual factors in their lives that influence the menopause journey.

CASE ENCOUNTER

I quickly look at the patient-filled form before I knock on the exam door, and I see that the patient has checked off that she has hot flashes, night sweats, and I make a mental note, she’s menopausal. I already have a preliminary plan to give this patient hormone therapy. I open the door, and I see that she’s Black. I know, based upon the data from SWAN and others, that her menopause means longer duration, more severe vasomotor symptoms. I have already teed up a prescription to go to the pharmacy.

The problem is, I have not even talked to her. She may actually nod her head, saying that she is going to go to the pharmacy, but she may never pick up that prescription. She likely leaves my office feeling unheard; her needs are unmet. I move onto the next patient. I feel good, but in actuality, I didn’t hear her. I have provided her bias and stereotyped care. I missed an opportunity to truly engage this patient and her care, and my good intentions of following the literature about her experience in menopause have contributed quite likely to her increased morbidity and mortality, her increased cardiovascular disease risk, all because I have not held space for her cultural identity.

References

1. Harlow SD, Burnett-Bowie SM, Greendale GA, et al. Disparities in reproductive aging and midlife health between Black and White women: the Study of Women’s Health Across the Nation (SWAN). Women’s Midlife Health. 2022;8:3. doi: 10.1186/s40695-022-00073-y.
2. Chlebowski RT, Aragaki AK, Anderson GL, et al. Forty-year trends in menopausal hormone therapy use and breast cancer incidence among postmenopausal black and white women. Cancer. 2020;126:2956-2964. doi: 10.1002/ cncr.32846.
3. Weng HH, McBride CM, Bosworth HB, et al. Racial differences in physician recommendation of hormone replacement therapy. Prev Med. 2001;33:668673. doi: 10.1006/pmed.2001.0943.
4. Williams M, Richard-Davis G, Williams PL, et al. A review of African American women’s experiences in menopause. Menopause. 2022;29:1331-1337. doi: 10.1097/GME.0000000000002060.
5. Im EO. Ethnic differences in symptoms experienced during the menopausal transition. Health Care Women Int. 2009;30:339-355. doi: 10.1080/07399330802695002.

Medical professionals are well aware that civil liability (malpractice) may incur when a patient is harmed because of carelessness (negligence). Recent criminal charges against physicians and a nurse, however, have called medical professionals’ attention to the fact that they also may face criminal charges for inappropriate practice.

We cite 2 cases in which criminal liability resulted from bad medical practice. In both instances, there was considerable concern among medical professionals that criminal charges for making a mistake would make it difficult to practice without fear of criminal charges. One concern is that criminal charges could drive good people out of the profession or make them too cautious.¹

We look more closely at those 2 cases in which criminal liability was imposed. These cases are outliers. Relatively few criminal cases against medical professionals are based on the quality of care. (There are, however, more criminal charges related to fraudulent billing and other insurance fraud, kickbacks, Medicare and Medicaid abuse, and the like.²) At the same time, the criminal law does not stop at the front door of a clinic or hospital.³ When medical professionals engage in seriously inappropriate health care conduct that directly harms someone, criminal liability may result.⁴

Anatomy of a crime

Crimes generally require a specific mental state (mens rea) and an act (actus reus). The law specifies the mental state required for conviction. It can range from premeditation—once commonly called “malice aforethought”—to negligence. The mens rea requirement is an essential element of the crime—as we will see in the discussion of the prescription drug cases. A few offenses do not require even negligence, but overwhelmingly, crimes require something more than simple negligence.⁵

The act requirement is generally obvious, such as firing a gun, driving while intoxicated, or recklessly giving inappropriate medication to a patient. It may include “attempts,” crimes where an act was not completed. For example, attempted murder or conspiracy to commit do not require a completed offense, only intent plus overt acts toward carrying out the crime. Similarly, the wrongful act usually has to produce some harm, but again there are exceptions (attempts). To obtain a conviction, the prosecution must prove all of the elements of the crime, including the required mens rea, beyond a reasonable doubt.⁶

With this general background, we turn to the first case, in which the charge was a form of homicide. Please note that the following case description was derived from news descriptions of the case, because juries do not publish opinions concerning their conclusions and court documents are unavailable. The public reports therefore may contain factual gaps and errors.

CASE 1 Patient dies after nurse administers wrong drug

RaDonda Vaught, a 38-year-old experienced registered nurse employed at Vanderbilt University Medical Center (VUMC) in the intensive care unit (ICU), was providing care for a 76-year-old patient who was admitted to VUMC’s ICU in December 2017 in association with a brain injury. The brain injury involved a fall with resultant subdural hematoma. In preparation for a positron emission tomography (PET) scan to assess the patient’s injury, the physician team prescribed the sedative Versed (midazolam) because of the patient’s claustrophobia. During the course of treatment, Ms. Vaught inadvertently administered the wrong drug, a fatal dose of the muscle relaxant vecuronium, to the patient, which resulted in the patient being unable to breathe. Apparently, Ms. Vaught had been unable to find the midazolam and disengaged a safeguard, proceeding into override mode, and thus vecuronium was dispensed. By the time the error was noticed, the patient was already in cardiac arrest with resultant brain damage (partial brain death). The patient died soon thereafter.

How this medication error occurred

The medication error occurred when Ms. Vaught overrode a computer in the medical system when she could not find the “Versed” entry and typed in “VE,” which was the abbreviation for vecuronium. The prosecutors in the case stated that she failed to distinguish that vecuronium is dispensed as a powder and Versed as a liquid formula. The vecuronium has a red cap, which warns that it is a paralyzing agent. Ms. Vaught ignored these red flags, according to the prosecutors. Furthermore, the lawsuit filing documented her discussion that she was “distracted with something” at the time and admitted to overriding the medication warning.

Continue to: The charges in this case...

 

 

The charges in this case

The charges revolved around “criminally negligent homicide and gross neglect of an impaired adult,” the most notable charge being criminally negligent homicide. Potential consequences were up to an 8 years’ prison sentence.⁷

Furthermore, the Tennessee Board of Nursing revoked Ms. Vaught’s license in July 2021.⁸ The Board also reportedly fined her $3,000.⁹

The criminal proceedings were filed in Davidson County Criminal Court, with Judge Jennifer Smith presiding. Ms. Vaught repeatedly manifested remorse for the event. The patient’s family, including her son Michael and her daughters-in-law, provided tearful testimonies at the hearing. Ms. Vaught repeatedly cried during the testimonies. The nurse did not provide an apology, according to one daughter-in-law. The news media reported that the family did not want jail time for Ms. Vaught.⁷ Nurses across the country were “jolted,” as expressed by the news media.¹⁰

Why the controversy?

The entire issue of medical errors continues to be discussed among both the medical and the legal professions. To have a nursing personnel held to the level of criminal liability is unusual.

It was clear that Ms. Vaught took responsibility for her actions, and neither the prosecutors nor defendant attorneys sensed any evidence of malice on her part. On the other hand, there was enough evidence and concern for District Attorney Glenn Funk to proceed with prosecution-related action. Ms. Vaught was facing years in prison if convicted.

WHAT’S THE VERDICT?

In March 2022, the jury convicted Ms. Vaught of criminally negligent homicide—but not of reckless homicide, a more serious offense.

Judge Smith granted a judicial diversion, that is, the conviction would be expunged from the record if Ms. Vaught completed a 3-year probation. Judge Smith noted the “credible remorse expressed by Nurse Vaught” and went on to state, “this is a terrible, terrible, mistake and there have been consequences to the defendant.” In the courtroom, Ms. Vaught apologized to the patient’s family and conveyed that she will “forever be haunted by her role in the (patient’s) passing.”

Overall, this served as an opportunity for health care workers to address oftentimes poor working conditions, which have been exacerbated by the COVID-19 pandemic.

The Davidson County District Attorney’s office conveyed that this was one case of a careless nurse and not a reflection of the nursing profession. The prosecutors were in accord with a probation verdict. The family felt that their mother, the patient, would not want to see the nurse serve a jail sentence: “Mom was a very forgiving person.”

The patient’s cause of death was listed as “intracerebral hemorrhage and cardiac arrest.” One year later, a new death certificate was issued and noted vecuronium intoxication as the cause of death.

Continue to: The health care institution’s involvement...

The health care institution’s involvement

Approximately 1 year after an apparent anonymous tip was made to health care officials, an unscheduled state and federal investigation, with the threat of possible sanctions, occurred at the VUMC. This was predicated on the criminal indictment related to Ms. Vaught. In the end, her nursing license was revoked, as noted earlier. The family earlier reached an out-of-court settlement with the hospital and there were a number of problems identified at the university medical center.¹¹

Legal principles in the case

Most criminal cases are state cases. Crimes are defined in state statutes, and the trial takes place in state courts. Thus, crimes are defined a little differently from state to state. Ms. Vaught, for example, was tried in Tennessee under the laws of that state.

Homicide involves the killing of a human being. It may not be a crime. For example, there is “justifiable homicide,” such as self-defense. At the other extreme is first-degree murder, an intentional and planned killing. In this case, Ms. Vaught was charged with criminally negligent homicide, which is usually the least serious of criminal homicides but is still a felony. (Some states have misdemeanor manslaughter, which was not an issue in this case.) In some states, criminally negligent homicide is sometimes referred to as involuntary manslaughter. The mens rea for involuntary manslaughter is generally recklessness or “criminal negligence.” This crime goes by various names depending on the state, but involuntary manslaughter and criminally negligent homicide are common names.

Ordinary negligence versus criminal negligence. Criminal negligence is usually considered a more serious mistake than ordinary negligence. This is where there is a difference between civil malpractice negligence and criminal negligence. Criminal negligence is somewhat more careless than ordinary negligence. To use a driving example, if Dr. A was driving home from the hospital, missed seeing a red light, and killed Joe Pedestrian, it could be ordinary negligence. If, however, Dr. B was texting or drinking while driving, causing Dr. B to be distracted and miss seeing the red light, killing a pedestrian, it could be criminal negligence and result in the conviction for the homicide. Of course, in either case there could be civil liability for causing the death.

Applying these legal principles to the reported facts in Ms. Vaught’s case, it appears there was more than simple negligence. That is, the nurse was more than careless. Using “VE” for the wrong drug might have been negligent. In addition, however, she disengaged a safeguard meant to prevent wrongful use of the drug, failed to notice that the drug was a powder instead of a liquid, and ignored the red cap warning that the drug was a paralyzing agent. It becomes apparent why the jury could have found aggravated or criminal negligence.

It is worth emphasizing that in this case, the criminal charges were unusual. For years, studies have suggested that many deaths result from medical errors. The Institute of Medicine famously said that the number of deaths from medical errors was equivalent to that of a 747 airplane crashing every day.^12,13 These events result in a relatively small number of malpractice actions but an infinitesimally small number of homicide charges. Among other things, prosecutors are reluctant to pursue such cases regarding acts carried out as part of clinical duties unless there is strong evidence, and grand juries may be reluctant to indict medical professionals.¹⁴

Nonetheless, medical professionals ultimately can be criminally responsible for deaths resulting from intentional, or criminally negligent, careless practice. Such liability should not dissuade nurses or others from medical practice any more than the much more common homicide charges that can occur from driving an automobile carelessly that results in someone’s death. A fundamental purpose of the criminal law is to disincentivize unnecessarily harmful (deadly) conduct, whether it is distracted driving or distracted nursing.

Continue to: The drug-prescribing crimes...

The drug-prescribing crimes

The US Supreme Court considered a much different kind of criminal medical practice in 2 (consolidated) cases in its 2021–2022 Term. Physicians in 2 states were each tried and convicted of federal charges of illegally dispensing or distributing (prescribing) controlled substances.¹⁵ A federal statute makes it a felony for a physician, or others, “except as authorized” to “knowingly or intentionally distribute, or dispense a controlled substance.”¹⁶ Federal regulations clarify the statute. The regulation provides that a prescription is authorized only if a doctor issues it “for a legitimate medical purpose . . . acting in the usual course of professional practice.”¹⁷

CASE 2 Physicians charged with overprescribing controlled substances

In these 2 drug-prescribing cases, the physicians had grossly overprescribed the opioids. One reportedly wrote prescriptions in 2 states in exchange for payments in cash or, infrequently, firearms, approximating the cost of the prescriptions to street drugs. The other had a clinic that, over about 4 years, issued 300,000 prescriptions for controlled substances and was a significant source for some kinds of fentanyl.¹⁸

WHAT’S THE VERDICT?

In each trial, the juries found the defendant guilty of improper distribution of controlled substances. Although the charges were not homicides, the sentencing judges were much more severe than the court had been in the nursing case discussed above. One physician received a prison term of 20 years, the other, a 25-year term. These undoubtedly reflect both the outrageous conduct and the likely great harm the defendants did.

The Supreme Court heard the cases

The Supreme Court reversed these physicians’ convictions. The Court held that the lower courts had not correctly described for the juries the mens rea required for a conviction under these charges. The Supreme Court held that to be convicted of these offenses, the government had to prove “beyond a reasonable doubt that the defendant [physician] knew that he or she was acting in an unauthorized manner.”¹⁹ Both can be retried and probably will be unless they reach a plea agreement with the federal government. Nonetheless, the Court established a very high standard. Carelessness is not enough, but rather “knowingly” acting in an unauthorized way is required. Although these physicians were prosecuted under federal law, other physicians have been prosecuted under state laws limiting the distribution of controlled substances.²⁰

Some physicians have expressed concern that the Supreme Court, in these cases, made the practice of medicine more dangerous for physicians (the threat of criminal sanctions) and patients (making it more difficult to obtain pain control, for example).^21,22 That view may be overly pessimistic for 2 reasons. First, the Court actually made it more difficult to convict physicians of writing excessive prescriptions. It did so by setting a higher mens rea standard than lower courts were using, that is, the physician had to “knowingly” act in an unauthorized way. Because “knowingly” can be implied by the circumstances, taking guns or cash would be evidence that the physician knowingly misprescribed.

More fundamentally, the actions of these physicians appear to be well outside even a generous legitimate level of controlled substance prescription. These convictions should not be misunderstood as a way of federal courts to crack down on pain medications. However, the original convictions are a warning to the small handful who grossly overprescribe controlled substances.

Lessons about criminal law and the practice of medicine

Medical professionals’ strong reaction to criminal charges is understandable. Criminal charges can result in jail time (the physicians involved in the controlled substance case were sentenced to 20 years or more) and hefty fines; bring social and professional disapprobation; may lead to license discipline; and are terribly disruptive even for those found not guilty. To make matters worse, malpractice insurance ordinarily does not cover criminal charges, so any fines and the cost of defense are likely out of pocket for those charged—and that can be very expensive. Therefore, the strong reaction to the cases we have described is understandable.

At the same time, the probability of criminal charges against medical personnel for their medical treatment is very low compared with, for example, fraudulent billing, their driving habits, or tax avoidance. Criminal charges are much more likely to arise from insurance fraud, Medicare or Medicaid dishonesty, kickbacks, false statements, and similar corruption crimes rather than inadequate practice. In the cases we examined here, there is an enhanced or aggravated negligence in one case and grossly inappropriate prescribing in the others (which the Supreme Court held must be “knowingly” wrong).

Finally, there is an irony. Medical professionals worried about practice-related criminal charges should be thankful for the malpractice system. Civil malpractice is, as a practical matter, an alternative for patients who believe they were mistreated or harmed by physicians or other providers. They have the option of finding a private attorney to file a civil complaint. In the absence of that system, they would be much more likely to take their grievance and complaint to the prosecutor to seek answers and retribution. Criminal law and civil liability are each a way of allowing someone harmed by another to seek redress. Both are intended to deter harmful conduct and provide some individual and social retribution for such behavior. The civil system, of course, also provides the potential for compensation to those injured. An injured patient without the possibility of a civil suit sometimes would turn to the criminal system for satisfaction. This way, the malpractice system is a better alternative to criminal charges. ●

Medical professionals are well aware that civil liability (malpractice) may incur when a patient is harmed because of carelessness (negligence). Recent criminal charges against physicians and a nurse, however, have called medical professionals’ attention to the fact that they also may face criminal charges for inappropriate practice.

We cite 2 cases in which criminal liability resulted from bad medical practice. In both instances, there was considerable concern among medical professionals that criminal charges for making a mistake would make it difficult to practice without fear of criminal charges. One concern is that criminal charges could drive good people out of the profession or make them too cautious.¹

We look more closely at those 2 cases in which criminal liability was imposed. These cases are outliers. Relatively few criminal cases against medical professionals are based on the quality of care. (There are, however, more criminal charges related to fraudulent billing and other insurance fraud, kickbacks, Medicare and Medicaid abuse, and the like.²) At the same time, the criminal law does not stop at the front door of a clinic or hospital.³ When medical professionals engage in seriously inappropriate health care conduct that directly harms someone, criminal liability may result.⁴

Anatomy of a crime

Crimes generally require a specific mental state (mens rea) and an act (actus reus). The law specifies the mental state required for conviction. It can range from premeditation—once commonly called “malice aforethought”—to negligence. The mens rea requirement is an essential element of the crime—as we will see in the discussion of the prescription drug cases. A few offenses do not require even negligence, but overwhelmingly, crimes require something more than simple negligence.⁵

The act requirement is generally obvious, such as firing a gun, driving while intoxicated, or recklessly giving inappropriate medication to a patient. It may include “attempts,” crimes where an act was not completed. For example, attempted murder or conspiracy to commit do not require a completed offense, only intent plus overt acts toward carrying out the crime. Similarly, the wrongful act usually has to produce some harm, but again there are exceptions (attempts). To obtain a conviction, the prosecution must prove all of the elements of the crime, including the required mens rea, beyond a reasonable doubt.⁶

With this general background, we turn to the first case, in which the charge was a form of homicide. Please note that the following case description was derived from news descriptions of the case, because juries do not publish opinions concerning their conclusions and court documents are unavailable. The public reports therefore may contain factual gaps and errors.

CASE 1 Patient dies after nurse administers wrong drug

RaDonda Vaught, a 38-year-old experienced registered nurse employed at Vanderbilt University Medical Center (VUMC) in the intensive care unit (ICU), was providing care for a 76-year-old patient who was admitted to VUMC’s ICU in December 2017 in association with a brain injury. The brain injury involved a fall with resultant subdural hematoma. In preparation for a positron emission tomography (PET) scan to assess the patient’s injury, the physician team prescribed the sedative Versed (midazolam) because of the patient’s claustrophobia. During the course of treatment, Ms. Vaught inadvertently administered the wrong drug, a fatal dose of the muscle relaxant vecuronium, to the patient, which resulted in the patient being unable to breathe. Apparently, Ms. Vaught had been unable to find the midazolam and disengaged a safeguard, proceeding into override mode, and thus vecuronium was dispensed. By the time the error was noticed, the patient was already in cardiac arrest with resultant brain damage (partial brain death). The patient died soon thereafter.

How this medication error occurred

The medication error occurred when Ms. Vaught overrode a computer in the medical system when she could not find the “Versed” entry and typed in “VE,” which was the abbreviation for vecuronium. The prosecutors in the case stated that she failed to distinguish that vecuronium is dispensed as a powder and Versed as a liquid formula. The vecuronium has a red cap, which warns that it is a paralyzing agent. Ms. Vaught ignored these red flags, according to the prosecutors. Furthermore, the lawsuit filing documented her discussion that she was “distracted with something” at the time and admitted to overriding the medication warning.

Continue to: The charges in this case...

 

 

The charges in this case

The charges revolved around “criminally negligent homicide and gross neglect of an impaired adult,” the most notable charge being criminally negligent homicide. Potential consequences were up to an 8 years’ prison sentence.⁷

Furthermore, the Tennessee Board of Nursing revoked Ms. Vaught’s license in July 2021.⁸ The Board also reportedly fined her $3,000.⁹

The criminal proceedings were filed in Davidson County Criminal Court, with Judge Jennifer Smith presiding. Ms. Vaught repeatedly manifested remorse for the event. The patient’s family, including her son Michael and her daughters-in-law, provided tearful testimonies at the hearing. Ms. Vaught repeatedly cried during the testimonies. The nurse did not provide an apology, according to one daughter-in-law. The news media reported that the family did not want jail time for Ms. Vaught.⁷ Nurses across the country were “jolted,” as expressed by the news media.¹⁰

Why the controversy?

The entire issue of medical errors continues to be discussed among both the medical and the legal professions. To have a nursing personnel held to the level of criminal liability is unusual.

It was clear that Ms. Vaught took responsibility for her actions, and neither the prosecutors nor defendant attorneys sensed any evidence of malice on her part. On the other hand, there was enough evidence and concern for District Attorney Glenn Funk to proceed with prosecution-related action. Ms. Vaught was facing years in prison if convicted.

WHAT’S THE VERDICT?

In March 2022, the jury convicted Ms. Vaught of criminally negligent homicide—but not of reckless homicide, a more serious offense.

Judge Smith granted a judicial diversion, that is, the conviction would be expunged from the record if Ms. Vaught completed a 3-year probation. Judge Smith noted the “credible remorse expressed by Nurse Vaught” and went on to state, “this is a terrible, terrible, mistake and there have been consequences to the defendant.” In the courtroom, Ms. Vaught apologized to the patient’s family and conveyed that she will “forever be haunted by her role in the (patient’s) passing.”

Overall, this served as an opportunity for health care workers to address oftentimes poor working conditions, which have been exacerbated by the COVID-19 pandemic.

The Davidson County District Attorney’s office conveyed that this was one case of a careless nurse and not a reflection of the nursing profession. The prosecutors were in accord with a probation verdict. The family felt that their mother, the patient, would not want to see the nurse serve a jail sentence: “Mom was a very forgiving person.”

The patient’s cause of death was listed as “intracerebral hemorrhage and cardiac arrest.” One year later, a new death certificate was issued and noted vecuronium intoxication as the cause of death.

Continue to: The health care institution’s involvement...

The health care institution’s involvement

Approximately 1 year after an apparent anonymous tip was made to health care officials, an unscheduled state and federal investigation, with the threat of possible sanctions, occurred at the VUMC. This was predicated on the criminal indictment related to Ms. Vaught. In the end, her nursing license was revoked, as noted earlier. The family earlier reached an out-of-court settlement with the hospital and there were a number of problems identified at the university medical center.¹¹

Legal principles in the case

Most criminal cases are state cases. Crimes are defined in state statutes, and the trial takes place in state courts. Thus, crimes are defined a little differently from state to state. Ms. Vaught, for example, was tried in Tennessee under the laws of that state.

Homicide involves the killing of a human being. It may not be a crime. For example, there is “justifiable homicide,” such as self-defense. At the other extreme is first-degree murder, an intentional and planned killing. In this case, Ms. Vaught was charged with criminally negligent homicide, which is usually the least serious of criminal homicides but is still a felony. (Some states have misdemeanor manslaughter, which was not an issue in this case.) In some states, criminally negligent homicide is sometimes referred to as involuntary manslaughter. The mens rea for involuntary manslaughter is generally recklessness or “criminal negligence.” This crime goes by various names depending on the state, but involuntary manslaughter and criminally negligent homicide are common names.

Ordinary negligence versus criminal negligence. Criminal negligence is usually considered a more serious mistake than ordinary negligence. This is where there is a difference between civil malpractice negligence and criminal negligence. Criminal negligence is somewhat more careless than ordinary negligence. To use a driving example, if Dr. A was driving home from the hospital, missed seeing a red light, and killed Joe Pedestrian, it could be ordinary negligence. If, however, Dr. B was texting or drinking while driving, causing Dr. B to be distracted and miss seeing the red light, killing a pedestrian, it could be criminal negligence and result in the conviction for the homicide. Of course, in either case there could be civil liability for causing the death.

Applying these legal principles to the reported facts in Ms. Vaught’s case, it appears there was more than simple negligence. That is, the nurse was more than careless. Using “VE” for the wrong drug might have been negligent. In addition, however, she disengaged a safeguard meant to prevent wrongful use of the drug, failed to notice that the drug was a powder instead of a liquid, and ignored the red cap warning that the drug was a paralyzing agent. It becomes apparent why the jury could have found aggravated or criminal negligence.

It is worth emphasizing that in this case, the criminal charges were unusual. For years, studies have suggested that many deaths result from medical errors. The Institute of Medicine famously said that the number of deaths from medical errors was equivalent to that of a 747 airplane crashing every day.^12,13 These events result in a relatively small number of malpractice actions but an infinitesimally small number of homicide charges. Among other things, prosecutors are reluctant to pursue such cases regarding acts carried out as part of clinical duties unless there is strong evidence, and grand juries may be reluctant to indict medical professionals.¹⁴

Nonetheless, medical professionals ultimately can be criminally responsible for deaths resulting from intentional, or criminally negligent, careless practice. Such liability should not dissuade nurses or others from medical practice any more than the much more common homicide charges that can occur from driving an automobile carelessly that results in someone’s death. A fundamental purpose of the criminal law is to disincentivize unnecessarily harmful (deadly) conduct, whether it is distracted driving or distracted nursing.

Continue to: The drug-prescribing crimes...

The drug-prescribing crimes

The US Supreme Court considered a much different kind of criminal medical practice in 2 (consolidated) cases in its 2021–2022 Term. Physicians in 2 states were each tried and convicted of federal charges of illegally dispensing or distributing (prescribing) controlled substances.¹⁵ A federal statute makes it a felony for a physician, or others, “except as authorized” to “knowingly or intentionally distribute, or dispense a controlled substance.”¹⁶ Federal regulations clarify the statute. The regulation provides that a prescription is authorized only if a doctor issues it “for a legitimate medical purpose . . . acting in the usual course of professional practice.”¹⁷

CASE 2 Physicians charged with overprescribing controlled substances

In these 2 drug-prescribing cases, the physicians had grossly overprescribed the opioids. One reportedly wrote prescriptions in 2 states in exchange for payments in cash or, infrequently, firearms, approximating the cost of the prescriptions to street drugs. The other had a clinic that, over about 4 years, issued 300,000 prescriptions for controlled substances and was a significant source for some kinds of fentanyl.¹⁸

WHAT’S THE VERDICT?

In each trial, the juries found the defendant guilty of improper distribution of controlled substances. Although the charges were not homicides, the sentencing judges were much more severe than the court had been in the nursing case discussed above. One physician received a prison term of 20 years, the other, a 25-year term. These undoubtedly reflect both the outrageous conduct and the likely great harm the defendants did.

The Supreme Court heard the cases

The Supreme Court reversed these physicians’ convictions. The Court held that the lower courts had not correctly described for the juries the mens rea required for a conviction under these charges. The Supreme Court held that to be convicted of these offenses, the government had to prove “beyond a reasonable doubt that the defendant [physician] knew that he or she was acting in an unauthorized manner.”¹⁹ Both can be retried and probably will be unless they reach a plea agreement with the federal government. Nonetheless, the Court established a very high standard. Carelessness is not enough, but rather “knowingly” acting in an unauthorized way is required. Although these physicians were prosecuted under federal law, other physicians have been prosecuted under state laws limiting the distribution of controlled substances.²⁰

Some physicians have expressed concern that the Supreme Court, in these cases, made the practice of medicine more dangerous for physicians (the threat of criminal sanctions) and patients (making it more difficult to obtain pain control, for example).^21,22 That view may be overly pessimistic for 2 reasons. First, the Court actually made it more difficult to convict physicians of writing excessive prescriptions. It did so by setting a higher mens rea standard than lower courts were using, that is, the physician had to “knowingly” act in an unauthorized way. Because “knowingly” can be implied by the circumstances, taking guns or cash would be evidence that the physician knowingly misprescribed.

More fundamentally, the actions of these physicians appear to be well outside even a generous legitimate level of controlled substance prescription. These convictions should not be misunderstood as a way of federal courts to crack down on pain medications. However, the original convictions are a warning to the small handful who grossly overprescribe controlled substances.

Lessons about criminal law and the practice of medicine

Medical professionals’ strong reaction to criminal charges is understandable. Criminal charges can result in jail time (the physicians involved in the controlled substance case were sentenced to 20 years or more) and hefty fines; bring social and professional disapprobation; may lead to license discipline; and are terribly disruptive even for those found not guilty. To make matters worse, malpractice insurance ordinarily does not cover criminal charges, so any fines and the cost of defense are likely out of pocket for those charged—and that can be very expensive. Therefore, the strong reaction to the cases we have described is understandable.

At the same time, the probability of criminal charges against medical personnel for their medical treatment is very low compared with, for example, fraudulent billing, their driving habits, or tax avoidance. Criminal charges are much more likely to arise from insurance fraud, Medicare or Medicaid dishonesty, kickbacks, false statements, and similar corruption crimes rather than inadequate practice. In the cases we examined here, there is an enhanced or aggravated negligence in one case and grossly inappropriate prescribing in the others (which the Supreme Court held must be “knowingly” wrong).

Finally, there is an irony. Medical professionals worried about practice-related criminal charges should be thankful for the malpractice system. Civil malpractice is, as a practical matter, an alternative for patients who believe they were mistreated or harmed by physicians or other providers. They have the option of finding a private attorney to file a civil complaint. In the absence of that system, they would be much more likely to take their grievance and complaint to the prosecutor to seek answers and retribution. Criminal law and civil liability are each a way of allowing someone harmed by another to seek redress. Both are intended to deter harmful conduct and provide some individual and social retribution for such behavior. The civil system, of course, also provides the potential for compensation to those injured. An injured patient without the possibility of a civil suit sometimes would turn to the criminal system for satisfaction. This way, the malpractice system is a better alternative to criminal charges. ●

Medical professionals are well aware that civil liability (malpractice) may incur when a patient is harmed because of carelessness (negligence). Recent criminal charges against physicians and a nurse, however, have called medical professionals’ attention to the fact that they also may face criminal charges for inappropriate practice.

We cite 2 cases in which criminal liability resulted from bad medical practice. In both instances, there was considerable concern among medical professionals that criminal charges for making a mistake would make it difficult to practice without fear of criminal charges. One concern is that criminal charges could drive good people out of the profession or make them too cautious.¹

We look more closely at those 2 cases in which criminal liability was imposed. These cases are outliers. Relatively few criminal cases against medical professionals are based on the quality of care. (There are, however, more criminal charges related to fraudulent billing and other insurance fraud, kickbacks, Medicare and Medicaid abuse, and the like.²) At the same time, the criminal law does not stop at the front door of a clinic or hospital.³ When medical professionals engage in seriously inappropriate health care conduct that directly harms someone, criminal liability may result.⁴

Anatomy of a crime

Crimes generally require a specific mental state (mens rea) and an act (actus reus). The law specifies the mental state required for conviction. It can range from premeditation—once commonly called “malice aforethought”—to negligence. The mens rea requirement is an essential element of the crime—as we will see in the discussion of the prescription drug cases. A few offenses do not require even negligence, but overwhelmingly, crimes require something more than simple negligence.⁵

The act requirement is generally obvious, such as firing a gun, driving while intoxicated, or recklessly giving inappropriate medication to a patient. It may include “attempts,” crimes where an act was not completed. For example, attempted murder or conspiracy to commit do not require a completed offense, only intent plus overt acts toward carrying out the crime. Similarly, the wrongful act usually has to produce some harm, but again there are exceptions (attempts). To obtain a conviction, the prosecution must prove all of the elements of the crime, including the required mens rea, beyond a reasonable doubt.⁶

With this general background, we turn to the first case, in which the charge was a form of homicide. Please note that the following case description was derived from news descriptions of the case, because juries do not publish opinions concerning their conclusions and court documents are unavailable. The public reports therefore may contain factual gaps and errors.

CASE 1 Patient dies after nurse administers wrong drug

RaDonda Vaught, a 38-year-old experienced registered nurse employed at Vanderbilt University Medical Center (VUMC) in the intensive care unit (ICU), was providing care for a 76-year-old patient who was admitted to VUMC’s ICU in December 2017 in association with a brain injury. The brain injury involved a fall with resultant subdural hematoma. In preparation for a positron emission tomography (PET) scan to assess the patient’s injury, the physician team prescribed the sedative Versed (midazolam) because of the patient’s claustrophobia. During the course of treatment, Ms. Vaught inadvertently administered the wrong drug, a fatal dose of the muscle relaxant vecuronium, to the patient, which resulted in the patient being unable to breathe. Apparently, Ms. Vaught had been unable to find the midazolam and disengaged a safeguard, proceeding into override mode, and thus vecuronium was dispensed. By the time the error was noticed, the patient was already in cardiac arrest with resultant brain damage (partial brain death). The patient died soon thereafter.

How this medication error occurred

The medication error occurred when Ms. Vaught overrode a computer in the medical system when she could not find the “Versed” entry and typed in “VE,” which was the abbreviation for vecuronium. The prosecutors in the case stated that she failed to distinguish that vecuronium is dispensed as a powder and Versed as a liquid formula. The vecuronium has a red cap, which warns that it is a paralyzing agent. Ms. Vaught ignored these red flags, according to the prosecutors. Furthermore, the lawsuit filing documented her discussion that she was “distracted with something” at the time and admitted to overriding the medication warning.

Continue to: The charges in this case...

 

 

The charges in this case

The charges revolved around “criminally negligent homicide and gross neglect of an impaired adult,” the most notable charge being criminally negligent homicide. Potential consequences were up to an 8 years’ prison sentence.⁷

Furthermore, the Tennessee Board of Nursing revoked Ms. Vaught’s license in July 2021.⁸ The Board also reportedly fined her $3,000.⁹

The criminal proceedings were filed in Davidson County Criminal Court, with Judge Jennifer Smith presiding. Ms. Vaught repeatedly manifested remorse for the event. The patient’s family, including her son Michael and her daughters-in-law, provided tearful testimonies at the hearing. Ms. Vaught repeatedly cried during the testimonies. The nurse did not provide an apology, according to one daughter-in-law. The news media reported that the family did not want jail time for Ms. Vaught.⁷ Nurses across the country were “jolted,” as expressed by the news media.¹⁰

Why the controversy?

The entire issue of medical errors continues to be discussed among both the medical and the legal professions. To have a nursing personnel held to the level of criminal liability is unusual.

It was clear that Ms. Vaught took responsibility for her actions, and neither the prosecutors nor defendant attorneys sensed any evidence of malice on her part. On the other hand, there was enough evidence and concern for District Attorney Glenn Funk to proceed with prosecution-related action. Ms. Vaught was facing years in prison if convicted.

WHAT’S THE VERDICT?

In March 2022, the jury convicted Ms. Vaught of criminally negligent homicide—but not of reckless homicide, a more serious offense.

Judge Smith granted a judicial diversion, that is, the conviction would be expunged from the record if Ms. Vaught completed a 3-year probation. Judge Smith noted the “credible remorse expressed by Nurse Vaught” and went on to state, “this is a terrible, terrible, mistake and there have been consequences to the defendant.” In the courtroom, Ms. Vaught apologized to the patient’s family and conveyed that she will “forever be haunted by her role in the (patient’s) passing.”

Overall, this served as an opportunity for health care workers to address oftentimes poor working conditions, which have been exacerbated by the COVID-19 pandemic.

The Davidson County District Attorney’s office conveyed that this was one case of a careless nurse and not a reflection of the nursing profession. The prosecutors were in accord with a probation verdict. The family felt that their mother, the patient, would not want to see the nurse serve a jail sentence: “Mom was a very forgiving person.”

The patient’s cause of death was listed as “intracerebral hemorrhage and cardiac arrest.” One year later, a new death certificate was issued and noted vecuronium intoxication as the cause of death.

Continue to: The health care institution’s involvement...

The health care institution’s involvement

Approximately 1 year after an apparent anonymous tip was made to health care officials, an unscheduled state and federal investigation, with the threat of possible sanctions, occurred at the VUMC. This was predicated on the criminal indictment related to Ms. Vaught. In the end, her nursing license was revoked, as noted earlier. The family earlier reached an out-of-court settlement with the hospital and there were a number of problems identified at the university medical center.¹¹

Legal principles in the case

Most criminal cases are state cases. Crimes are defined in state statutes, and the trial takes place in state courts. Thus, crimes are defined a little differently from state to state. Ms. Vaught, for example, was tried in Tennessee under the laws of that state.

Homicide involves the killing of a human being. It may not be a crime. For example, there is “justifiable homicide,” such as self-defense. At the other extreme is first-degree murder, an intentional and planned killing. In this case, Ms. Vaught was charged with criminally negligent homicide, which is usually the least serious of criminal homicides but is still a felony. (Some states have misdemeanor manslaughter, which was not an issue in this case.) In some states, criminally negligent homicide is sometimes referred to as involuntary manslaughter. The mens rea for involuntary manslaughter is generally recklessness or “criminal negligence.” This crime goes by various names depending on the state, but involuntary manslaughter and criminally negligent homicide are common names.

Ordinary negligence versus criminal negligence. Criminal negligence is usually considered a more serious mistake than ordinary negligence. This is where there is a difference between civil malpractice negligence and criminal negligence. Criminal negligence is somewhat more careless than ordinary negligence. To use a driving example, if Dr. A was driving home from the hospital, missed seeing a red light, and killed Joe Pedestrian, it could be ordinary negligence. If, however, Dr. B was texting or drinking while driving, causing Dr. B to be distracted and miss seeing the red light, killing a pedestrian, it could be criminal negligence and result in the conviction for the homicide. Of course, in either case there could be civil liability for causing the death.

Applying these legal principles to the reported facts in Ms. Vaught’s case, it appears there was more than simple negligence. That is, the nurse was more than careless. Using “VE” for the wrong drug might have been negligent. In addition, however, she disengaged a safeguard meant to prevent wrongful use of the drug, failed to notice that the drug was a powder instead of a liquid, and ignored the red cap warning that the drug was a paralyzing agent. It becomes apparent why the jury could have found aggravated or criminal negligence.

It is worth emphasizing that in this case, the criminal charges were unusual. For years, studies have suggested that many deaths result from medical errors. The Institute of Medicine famously said that the number of deaths from medical errors was equivalent to that of a 747 airplane crashing every day.^12,13 These events result in a relatively small number of malpractice actions but an infinitesimally small number of homicide charges. Among other things, prosecutors are reluctant to pursue such cases regarding acts carried out as part of clinical duties unless there is strong evidence, and grand juries may be reluctant to indict medical professionals.¹⁴

Nonetheless, medical professionals ultimately can be criminally responsible for deaths resulting from intentional, or criminally negligent, careless practice. Such liability should not dissuade nurses or others from medical practice any more than the much more common homicide charges that can occur from driving an automobile carelessly that results in someone’s death. A fundamental purpose of the criminal law is to disincentivize unnecessarily harmful (deadly) conduct, whether it is distracted driving or distracted nursing.

Continue to: The drug-prescribing crimes...

The drug-prescribing crimes

The US Supreme Court considered a much different kind of criminal medical practice in 2 (consolidated) cases in its 2021–2022 Term. Physicians in 2 states were each tried and convicted of federal charges of illegally dispensing or distributing (prescribing) controlled substances.¹⁵ A federal statute makes it a felony for a physician, or others, “except as authorized” to “knowingly or intentionally distribute, or dispense a controlled substance.”¹⁶ Federal regulations clarify the statute. The regulation provides that a prescription is authorized only if a doctor issues it “for a legitimate medical purpose . . . acting in the usual course of professional practice.”¹⁷

CASE 2 Physicians charged with overprescribing controlled substances

In these 2 drug-prescribing cases, the physicians had grossly overprescribed the opioids. One reportedly wrote prescriptions in 2 states in exchange for payments in cash or, infrequently, firearms, approximating the cost of the prescriptions to street drugs. The other had a clinic that, over about 4 years, issued 300,000 prescriptions for controlled substances and was a significant source for some kinds of fentanyl.¹⁸

WHAT’S THE VERDICT?

In each trial, the juries found the defendant guilty of improper distribution of controlled substances. Although the charges were not homicides, the sentencing judges were much more severe than the court had been in the nursing case discussed above. One physician received a prison term of 20 years, the other, a 25-year term. These undoubtedly reflect both the outrageous conduct and the likely great harm the defendants did.

The Supreme Court heard the cases

The Supreme Court reversed these physicians’ convictions. The Court held that the lower courts had not correctly described for the juries the mens rea required for a conviction under these charges. The Supreme Court held that to be convicted of these offenses, the government had to prove “beyond a reasonable doubt that the defendant [physician] knew that he or she was acting in an unauthorized manner.”¹⁹ Both can be retried and probably will be unless they reach a plea agreement with the federal government. Nonetheless, the Court established a very high standard. Carelessness is not enough, but rather “knowingly” acting in an unauthorized way is required. Although these physicians were prosecuted under federal law, other physicians have been prosecuted under state laws limiting the distribution of controlled substances.²⁰

Some physicians have expressed concern that the Supreme Court, in these cases, made the practice of medicine more dangerous for physicians (the threat of criminal sanctions) and patients (making it more difficult to obtain pain control, for example).^21,22 That view may be overly pessimistic for 2 reasons. First, the Court actually made it more difficult to convict physicians of writing excessive prescriptions. It did so by setting a higher mens rea standard than lower courts were using, that is, the physician had to “knowingly” act in an unauthorized way. Because “knowingly” can be implied by the circumstances, taking guns or cash would be evidence that the physician knowingly misprescribed.

More fundamentally, the actions of these physicians appear to be well outside even a generous legitimate level of controlled substance prescription. These convictions should not be misunderstood as a way of federal courts to crack down on pain medications. However, the original convictions are a warning to the small handful who grossly overprescribe controlled substances.

Lessons about criminal law and the practice of medicine

Medical professionals’ strong reaction to criminal charges is understandable. Criminal charges can result in jail time (the physicians involved in the controlled substance case were sentenced to 20 years or more) and hefty fines; bring social and professional disapprobation; may lead to license discipline; and are terribly disruptive even for those found not guilty. To make matters worse, malpractice insurance ordinarily does not cover criminal charges, so any fines and the cost of defense are likely out of pocket for those charged—and that can be very expensive. Therefore, the strong reaction to the cases we have described is understandable.

At the same time, the probability of criminal charges against medical personnel for their medical treatment is very low compared with, for example, fraudulent billing, their driving habits, or tax avoidance. Criminal charges are much more likely to arise from insurance fraud, Medicare or Medicaid dishonesty, kickbacks, false statements, and similar corruption crimes rather than inadequate practice. In the cases we examined here, there is an enhanced or aggravated negligence in one case and grossly inappropriate prescribing in the others (which the Supreme Court held must be “knowingly” wrong).

Finally, there is an irony. Medical professionals worried about practice-related criminal charges should be thankful for the malpractice system. Civil malpractice is, as a practical matter, an alternative for patients who believe they were mistreated or harmed by physicians or other providers. They have the option of finding a private attorney to file a civil complaint. In the absence of that system, they would be much more likely to take their grievance and complaint to the prosecutor to seek answers and retribution. Criminal law and civil liability are each a way of allowing someone harmed by another to seek redress. Both are intended to deter harmful conduct and provide some individual and social retribution for such behavior. The civil system, of course, also provides the potential for compensation to those injured. An injured patient without the possibility of a civil suit sometimes would turn to the criminal system for satisfaction. This way, the malpractice system is a better alternative to criminal charges. ●

Dr Harold Burstein, of the Dana-Farber Cancer Institute in Boston, Massachusetts, reports on studies in HR+/HER2- breast cancer presented at the 2022 San Antonio Breast Cancer Symposium. 

Dr Burstein reports on the phase 2 RIGHT Choice study, which is the first head-to-head comparison of endocrine therapy plus a CDK4/6 inhibitor vs chemotherapy for stage IV breast cancer. The results indicate that frontline therapy using the combination is superior to chemotherapy.  

Dr Burstein next comments on the phase 3 CAPItello-291 trial, which looked at a new AKT inhibitor, capivasertib. The study compared capivasertib plus fulvestrant vs fulvestrant alone and found that the combination provided meaningful improvements in progression-free survival. He then reports on the phase 2 SERENA-2 trial, which compared fulvestrant with camizestrant, an oral selective estrogen receptor degrader, in the second-line setting. The study showed that camizestrant was superior to fulvestrant.  

An update of the phase 3 monarchE trial showed an increasing benefit from adding abemaciclib to endocrine therapy in the adjuvant setting, regardless of the Ki-67 index. 

In closing, Dr Burstein discusses the POSITIVE trial, which indicated that endocrine therapy can be safely interrupted in women whose breast cancer is in remission and who are pursuing pregnancy.  

--

Harold J. Burstein, MD, PhD, Professor, Department of Medicine, Harvard Medical School; Medical Oncologist, Dana-Farber Cancer Institute, Boston, Massachusetts 

Harold J. Burstein, MD, PhD, has disclosed no relevant financial relationships. 

Dr Harold Burstein, of the Dana-Farber Cancer Institute in Boston, Massachusetts, reports on studies in HR+/HER2- breast cancer presented at the 2022 San Antonio Breast Cancer Symposium. 

Dr Burstein reports on the phase 2 RIGHT Choice study, which is the first head-to-head comparison of endocrine therapy plus a CDK4/6 inhibitor vs chemotherapy for stage IV breast cancer. The results indicate that frontline therapy using the combination is superior to chemotherapy.  

Dr Burstein next comments on the phase 3 CAPItello-291 trial, which looked at a new AKT inhibitor, capivasertib. The study compared capivasertib plus fulvestrant vs fulvestrant alone and found that the combination provided meaningful improvements in progression-free survival. He then reports on the phase 2 SERENA-2 trial, which compared fulvestrant with camizestrant, an oral selective estrogen receptor degrader, in the second-line setting. The study showed that camizestrant was superior to fulvestrant.  

An update of the phase 3 monarchE trial showed an increasing benefit from adding abemaciclib to endocrine therapy in the adjuvant setting, regardless of the Ki-67 index. 

In closing, Dr Burstein discusses the POSITIVE trial, which indicated that endocrine therapy can be safely interrupted in women whose breast cancer is in remission and who are pursuing pregnancy.  

--

Harold J. Burstein, MD, PhD, Professor, Department of Medicine, Harvard Medical School; Medical Oncologist, Dana-Farber Cancer Institute, Boston, Massachusetts 

Harold J. Burstein, MD, PhD, has disclosed no relevant financial relationships. 

Dr Harold Burstein, of the Dana-Farber Cancer Institute in Boston, Massachusetts, reports on studies in HR+/HER2- breast cancer presented at the 2022 San Antonio Breast Cancer Symposium. 

Dr Burstein reports on the phase 2 RIGHT Choice study, which is the first head-to-head comparison of endocrine therapy plus a CDK4/6 inhibitor vs chemotherapy for stage IV breast cancer. The results indicate that frontline therapy using the combination is superior to chemotherapy.  

Dr Burstein next comments on the phase 3 CAPItello-291 trial, which looked at a new AKT inhibitor, capivasertib. The study compared capivasertib plus fulvestrant vs fulvestrant alone and found that the combination provided meaningful improvements in progression-free survival. He then reports on the phase 2 SERENA-2 trial, which compared fulvestrant with camizestrant, an oral selective estrogen receptor degrader, in the second-line setting. The study showed that camizestrant was superior to fulvestrant.  

An update of the phase 3 monarchE trial showed an increasing benefit from adding abemaciclib to endocrine therapy in the adjuvant setting, regardless of the Ki-67 index. 

In closing, Dr Burstein discusses the POSITIVE trial, which indicated that endocrine therapy can be safely interrupted in women whose breast cancer is in remission and who are pursuing pregnancy.  

--

Harold J. Burstein, MD, PhD, Professor, Department of Medicine, Harvard Medical School; Medical Oncologist, Dana-Farber Cancer Institute, Boston, Massachusetts 

Harold J. Burstein, MD, PhD, has disclosed no relevant financial relationships. 

Dr Peter Martin, from Weill Cornell Medicine in New York, NY, highlights breakthroughs and developments in mantle cell lymphoma presented at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition. 

Dr Martin begins with the top-ranked abstract from the meeting, a European trial that looked at ibrutinib as a substitute for autologous stem cell transplantation (ASCT) in younger patients. The results suggest that the era of upfront ASCT may now be over. 

Next, he reports on a trial that investigated the addition of the second-generation BTK inhibitor acalabrutinib to lenalidomide and rituximab. The combination provided excellent clinical responses, indicating that mantle cell lymphoma patients may soon be able to avoid chemotherapy altogether. 

The next trial selected by Dr Martin examined whether the addition of lenalidomide to consolidation rituximab after first-line bendamustine-rituximab would improve survival outcomes. The study reported no additional benefit, at the cost of increased adverse events. 

Dr Martin closes by discussing two trials in the relapsed/refractory setting, one a phase 1 trial of the bispecific antibody glofitamab, the other a phase 1b-2 trial of venetoclax with lenalidomide and rituximab. Both showed encouraging results that point to potential future treatment strategies. 

--

Associate Professor of Medicine, Weill Cornell Medicine, New York, NY 

Peter Martin, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AstraZeneca; ADCT; BeiGene; Bristol Myers Squibb; Epizyme; Genentech; Gilead; Janssen; Takeda 

Dr Peter Martin, from Weill Cornell Medicine in New York, NY, highlights breakthroughs and developments in mantle cell lymphoma presented at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition. 

Dr Martin begins with the top-ranked abstract from the meeting, a European trial that looked at ibrutinib as a substitute for autologous stem cell transplantation (ASCT) in younger patients. The results suggest that the era of upfront ASCT may now be over. 

Next, he reports on a trial that investigated the addition of the second-generation BTK inhibitor acalabrutinib to lenalidomide and rituximab. The combination provided excellent clinical responses, indicating that mantle cell lymphoma patients may soon be able to avoid chemotherapy altogether. 

The next trial selected by Dr Martin examined whether the addition of lenalidomide to consolidation rituximab after first-line bendamustine-rituximab would improve survival outcomes. The study reported no additional benefit, at the cost of increased adverse events. 

Dr Martin closes by discussing two trials in the relapsed/refractory setting, one a phase 1 trial of the bispecific antibody glofitamab, the other a phase 1b-2 trial of venetoclax with lenalidomide and rituximab. Both showed encouraging results that point to potential future treatment strategies. 

--

Associate Professor of Medicine, Weill Cornell Medicine, New York, NY 

Peter Martin, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AstraZeneca; ADCT; BeiGene; Bristol Myers Squibb; Epizyme; Genentech; Gilead; Janssen; Takeda 

Dr Peter Martin, from Weill Cornell Medicine in New York, NY, highlights breakthroughs and developments in mantle cell lymphoma presented at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition. 

Dr Martin begins with the top-ranked abstract from the meeting, a European trial that looked at ibrutinib as a substitute for autologous stem cell transplantation (ASCT) in younger patients. The results suggest that the era of upfront ASCT may now be over. 

Next, he reports on a trial that investigated the addition of the second-generation BTK inhibitor acalabrutinib to lenalidomide and rituximab. The combination provided excellent clinical responses, indicating that mantle cell lymphoma patients may soon be able to avoid chemotherapy altogether. 

The next trial selected by Dr Martin examined whether the addition of lenalidomide to consolidation rituximab after first-line bendamustine-rituximab would improve survival outcomes. The study reported no additional benefit, at the cost of increased adverse events. 

Dr Martin closes by discussing two trials in the relapsed/refractory setting, one a phase 1 trial of the bispecific antibody glofitamab, the other a phase 1b-2 trial of venetoclax with lenalidomide and rituximab. Both showed encouraging results that point to potential future treatment strategies. 

--

Associate Professor of Medicine, Weill Cornell Medicine, New York, NY 

Peter Martin, MD, has disclosed the following relevant financial relationships: 

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AstraZeneca; ADCT; BeiGene; Bristol Myers Squibb; Epizyme; Genentech; Gilead; Janssen; Takeda 

Test

Test

Test

This patient's clinical presentation and endoscopy findings are consistent with a diagnosis of recurrent MCL presenting as a colonic mass.

MCL is an aggressive type of non-Hodgkin lymphoma that accounts for approximately 5%-7% of all lymphomas. Nearly 80% of patients have extranodal involvement at initial presentation, occurring in sites such as the bone marrow, spleen, Waldeyer ring, and the gastrointestinal (GI) tract. Secondary GI involvement in MCL (involving nodal and/or other extranodal tissue) is common and may be detected at diagnosis and/or relapse. In several retrospective studies, the prevalence of secondary GI involvement in MCL ranged from 15% to 30%. However, in later studies, routine endoscopies in patients with untreated MCL showed GI involvement in up to 90% of patients, despite most patients not reporting GI symptoms.

The colon is the most commonly involved GI site; however, both the upper and lower GI tract from the stomach to the colon can be involved. Lymphomatous polyposis is the most common endoscopic presentation of MCL, but polyp, mass, or even normal-appearing mucosa may also be seen. 

New and emerging treatment options are helping to improve survival in patients with relapsed/refractory MCL. According to National Comprehensive Cancer Network guidelines, the preferred second-line and subsequent regimens are:

•    Bruton tyrosine kinase (BTK) inhibitors:

o    Acalabrutinib
o    Ibrutinib ± rituximab
o    Zanubrutinib

•    Lenalidomide + rituximab (if BTK inhibitor is contraindicated)

Other regimens that may be useful in certain circumstances are:

•    Bendamustine + rituximab (if not previously given)
•    Bendamustine + rituximab + cytarabine (RBAC500) (if not previously given)
•    Bortezomib ± rituximab
•    RDHA (rituximab, dexamethasone, cytarabine) + platinum (carboplatin, cisplatin, or oxaliplatin) (if not previously given)
•    GemOx (gemcitabine, oxaliplatin) + rituximab
•    Ibrutinib, lenalidomide, rituximab (category 2B)
•    Ibrutinib + venetoclax
•    Venetoclax, lenalidomide, rituximab (category 2B)
•    Venetoclax ± rituximab

Brexucabtagene autoleucel is suggested as third-line therapy, after chemoimmunotherapy and treatment with a BTK inhibitor. 

Timothy J. Voorhees, MD, MSCR, Assistant Professor of Internal Medicine - Clinical, Division of Hematology, The Ohio State University James Comprehensive Cancer Center, Columbus, OH.

Timothy J. Voorhees, MD, MSCR, has disclosed the following relevant financial relationships:
Received research grant from: AstraZeneca; Morphosys; Incyte; Recordati.

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

This patient's clinical presentation and endoscopy findings are consistent with a diagnosis of recurrent MCL presenting as a colonic mass.

MCL is an aggressive type of non-Hodgkin lymphoma that accounts for approximately 5%-7% of all lymphomas. Nearly 80% of patients have extranodal involvement at initial presentation, occurring in sites such as the bone marrow, spleen, Waldeyer ring, and the gastrointestinal (GI) tract. Secondary GI involvement in MCL (involving nodal and/or other extranodal tissue) is common and may be detected at diagnosis and/or relapse. In several retrospective studies, the prevalence of secondary GI involvement in MCL ranged from 15% to 30%. However, in later studies, routine endoscopies in patients with untreated MCL showed GI involvement in up to 90% of patients, despite most patients not reporting GI symptoms.

The colon is the most commonly involved GI site; however, both the upper and lower GI tract from the stomach to the colon can be involved. Lymphomatous polyposis is the most common endoscopic presentation of MCL, but polyp, mass, or even normal-appearing mucosa may also be seen. 

New and emerging treatment options are helping to improve survival in patients with relapsed/refractory MCL. According to National Comprehensive Cancer Network guidelines, the preferred second-line and subsequent regimens are:

•    Bruton tyrosine kinase (BTK) inhibitors:

o    Acalabrutinib
o    Ibrutinib ± rituximab
o    Zanubrutinib

•    Lenalidomide + rituximab (if BTK inhibitor is contraindicated)

Other regimens that may be useful in certain circumstances are:

•    Bendamustine + rituximab (if not previously given)
•    Bendamustine + rituximab + cytarabine (RBAC500) (if not previously given)
•    Bortezomib ± rituximab
•    RDHA (rituximab, dexamethasone, cytarabine) + platinum (carboplatin, cisplatin, or oxaliplatin) (if not previously given)
•    GemOx (gemcitabine, oxaliplatin) + rituximab
•    Ibrutinib, lenalidomide, rituximab (category 2B)
•    Ibrutinib + venetoclax
•    Venetoclax, lenalidomide, rituximab (category 2B)
•    Venetoclax ± rituximab

Brexucabtagene autoleucel is suggested as third-line therapy, after chemoimmunotherapy and treatment with a BTK inhibitor. 

Timothy J. Voorhees, MD, MSCR, Assistant Professor of Internal Medicine - Clinical, Division of Hematology, The Ohio State University James Comprehensive Cancer Center, Columbus, OH.

Timothy J. Voorhees, MD, MSCR, has disclosed the following relevant financial relationships:
Received research grant from: AstraZeneca; Morphosys; Incyte; Recordati.

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

This patient's clinical presentation and endoscopy findings are consistent with a diagnosis of recurrent MCL presenting as a colonic mass.

MCL is an aggressive type of non-Hodgkin lymphoma that accounts for approximately 5%-7% of all lymphomas. Nearly 80% of patients have extranodal involvement at initial presentation, occurring in sites such as the bone marrow, spleen, Waldeyer ring, and the gastrointestinal (GI) tract. Secondary GI involvement in MCL (involving nodal and/or other extranodal tissue) is common and may be detected at diagnosis and/or relapse. In several retrospective studies, the prevalence of secondary GI involvement in MCL ranged from 15% to 30%. However, in later studies, routine endoscopies in patients with untreated MCL showed GI involvement in up to 90% of patients, despite most patients not reporting GI symptoms.

The colon is the most commonly involved GI site; however, both the upper and lower GI tract from the stomach to the colon can be involved. Lymphomatous polyposis is the most common endoscopic presentation of MCL, but polyp, mass, or even normal-appearing mucosa may also be seen. 

New and emerging treatment options are helping to improve survival in patients with relapsed/refractory MCL. According to National Comprehensive Cancer Network guidelines, the preferred second-line and subsequent regimens are:

•    Bruton tyrosine kinase (BTK) inhibitors:

o    Acalabrutinib
o    Ibrutinib ± rituximab
o    Zanubrutinib

•    Lenalidomide + rituximab (if BTK inhibitor is contraindicated)

Other regimens that may be useful in certain circumstances are:

•    Bendamustine + rituximab (if not previously given)
•    Bendamustine + rituximab + cytarabine (RBAC500) (if not previously given)
•    Bortezomib ± rituximab
•    RDHA (rituximab, dexamethasone, cytarabine) + platinum (carboplatin, cisplatin, or oxaliplatin) (if not previously given)
•    GemOx (gemcitabine, oxaliplatin) + rituximab
•    Ibrutinib, lenalidomide, rituximab (category 2B)
•    Ibrutinib + venetoclax
•    Venetoclax, lenalidomide, rituximab (category 2B)
•    Venetoclax ± rituximab

Brexucabtagene autoleucel is suggested as third-line therapy, after chemoimmunotherapy and treatment with a BTK inhibitor. 

Timothy J. Voorhees, MD, MSCR, Assistant Professor of Internal Medicine - Clinical, Division of Hematology, The Ohio State University James Comprehensive Cancer Center, Columbus, OH.

Timothy J. Voorhees, MD, MSCR, has disclosed the following relevant financial relationships:
Received research grant from: AstraZeneca; Morphosys; Incyte; Recordati.

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

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 informa tion, contact [email protected].

Lithium carbonate is a mood stabilizer that is effective in the treatment of bipolar disorder, particularly in controlling mania.¹ Lithium can reduce the risk of suicide,² treat aggression and self-mutilating behavior,³ and prevent steroid-induced psychosis.⁴ It also can raise the white cell count in patients with clozapine-induced leukopenia.⁵

To prevent or lower the risk of relapse, the therapeutic plasma level of lithium should be regularly monitored to ensure an optimal concentration in the CNS. The highest tolerable level of lithium in the plasma is 0.6 to 0.8 mmol/L, with the optimal level ranging up to 1.2 mmol/L.⁶ Regular monitoring of renal function is also required to prevent renal toxicity, particularly if the plasma level exceeds 0.8 mmol/L.⁷ Because of lithium’s relatively narrow therapeutic index, its interaction with other medications, such as angiotensin-converting enzyme inhibitors, diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), and carbamazepine, can also precipitate lithium toxicity.⁸ We describe a lesson learned from a case of lithium toxicity in an otherwise healthy patient with bipolar disorder.

Case report

An otherwise healthy 39-year-old woman diagnosed with bipolar type I disorder was receiving valproate sodium 600 mg/d and olanzapine 10 mg/d. Despite improvement in her mood, she gained 11.6 kg following 6 months of treatment. As a result, olanzapine was switched to aripiprazole 10 mg/d that was later increased to 15 mg/d, and sodium valproate was gradually optimized up to 1,000 mg/d. She later complained of hair thinning and hair loss so she self-adjusted her medication dosages, which resulted in frequent relapses. Her mood stabilizer was changed from sodium valproate to lithium 600 mg/d.

Unfortunately, after taking lithium for 15 days, she returned to us with fever associated with reduced oral intake, poor sleep, bilateral upper limb rigidity, and bilateral hand tremor. She also complained of extreme thirst and fatigue but no vomiting or diarrhea. She had difficulty falling asleep and slept for only 1 to 2 hours a day. Her symptoms worsened when a general practitioner prescribed NSAIDs for her fever and body ache. Her tremors were later generalized, which made it difficult for her to take her oral medications and disturbed her speech and movement.

On evaluation, our patient appeared comfortable and not agitated. She was orientated to time, place, and person. Her blood pressure was 139/89 mmHg, heart rate was 104 bpm, and she was afebrile. She was dehydrated with minimal urine output. She had coarse tremor in her upper and lower limbs, which were hypertonic but did not display hyperreflexia or clonus. There was no nystagmus or ataxia. A mental state examination showed no signs of manic, hypomanic, or depressive symptoms. She had slurred speech, and her affect was restricted.

Blood investigation revealed a suprathreshold lithium level of 1.70 mmol/L (normal: 0.8 to 1.2 mmol/L). Biochemical parameters showed evidence of acute kidney injury (urea: 6.1 mmol/L; creatinine: 0.140 mmol/L), with no electrolyte imbalance. There was no evidence of hypothyroidism (thyroid-stimulating hormone: 14.9 mIU/L; free thyroxine: 9.9 pmol/L), hyperparathyroidism, or hypercalcemia. Autoimmune markers were positive for antinuclear antibody (titre 1:320) and anti-double stranded DNA (76.8 IU/mL). Apart from hair loss, she denied other symptoms associated with autoimmune disease, such as joint pain, butterfly rash, or persistent fatigue. Other routine blood investigations were within normal limits. Her urine protein throughout admission had shown persistent proteinuria ranging from 3+ to 4+. Electrocardiogram (ECG) showed normal sinus rhythm with no T wave inversion or QT prolongation.

Continue to: A detailed family history...

A detailed family history later confirmed a strong family history of renal disease: her mother had lupus nephritis with nephrotic syndrome, and her brother had died from complications of a rapidly progressive glomerulonephritis. Her renal function prior to lithium initiation was within normal limits (urea: 4.0 mmol/L; serum creatinine: 78 µmol/L).

In the ward, lithium and aripiprazole were discontinued, and she was hydrated. Combined care with the psychiatric and medical teams was established early to safeguard against potential CNS deterioration. She showed marked clinical improvement by Day 3, with the resolution of coarse tremor and rigidity as well as normalization of blood parameters. Her lithium level returned to a therapeutic level by Day 4 after lithium discontinuation, and her renal profile gradually normalized. She was restarted on aripiprazole 10 mg/d for her bipolar illness and responded well. She was discharged on Day 5 with a referral to the nephrology team for further intervention.

Lessons learned

This case highlights the issue of lithium safety in susceptible individuals and the importance of risk stratification in this group of patients. Lithium is an effective treatment for bipolar I disorder and has also been used as adjunctive treatment for major depressive disorder, schizoaffective disorder, treatment-resistant schizophrenia, anorexia nervosa and bulimia nervosa, and the control of chronic aggression.⁹ Lithium is completely absorbed by the gastrointestinal tract following ingestion, is not metabolized, and is eliminated almost entirely by the kidneys (though trace amounts may be found in feces and perspiration).

In our case, a detailed family history of renal disease was not adequately explored until our patient presented with signs suggestive of lithium toxicity. Our patient had been prescribed lithium 600 mg/d as a maintenance therapy. Upon starting lithium, her baseline biochemical parameters were within normal limits, and renal issues were not suspected. The hair thinning and hair loss she experienced could have been an adverse effect of valproate sodium or a manifestation of an underlying autoimmune disease. Coupled with the use of NSAIDs that could have precipitated acute kidney injury, her poor oral intake and dehydration during the acute illness further impaired lithium excretion, leading to a suprathreshold plasma level despite a low dose of lithium. Therefore, before prescribing lithium, a thorough medical and family history is needed, supplemented by an evaluation of renal function, serum electrolytes, and thyroid function to determine the starting dosage of lithium. Routine vital sign assessment and ECG should also be conducted, and concurrent medications and pregnancy status should be confirmed before prescribing lithium. Regular lithium level monitoring is essential.

Measuring a patient’s estimated glomerular filtration rate (eGFR) is recommended to validate renal status¹⁰ and classify and stage kidney disease.¹¹ Combining eGFR with blood urea nitrogen, serum creatinine, and urine microscopic analysis further improves the prediction of renal disease in early stages. We recommend considering a blood test for autoimmune markers in patients with clinical suspicion of autoimmune disease, in the presence of suggestive signs and symptoms, and/or in patients with a positive family history (Table).

Before starting lithium, in addition to conducting a detailed clinical evaluation, information about symptoms and the risk of lithium toxicity should be discussed with patients.¹² Our case serves as a timely reminder that the lack of suggestive biochemical parameters of renal disease should not rule out an underlying renal disease, and a strong family history of renal disease should warrant suspicion of a possible autoimmune origin.

We suggest that future studies evaluate the risks of lithium toxicity in susceptible groups of patients, such as those with family history of renal disease.

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 informa tion, contact [email protected].

Lithium carbonate is a mood stabilizer that is effective in the treatment of bipolar disorder, particularly in controlling mania.¹ Lithium can reduce the risk of suicide,² treat aggression and self-mutilating behavior,³ and prevent steroid-induced psychosis.⁴ It also can raise the white cell count in patients with clozapine-induced leukopenia.⁵

To prevent or lower the risk of relapse, the therapeutic plasma level of lithium should be regularly monitored to ensure an optimal concentration in the CNS. The highest tolerable level of lithium in the plasma is 0.6 to 0.8 mmol/L, with the optimal level ranging up to 1.2 mmol/L.⁶ Regular monitoring of renal function is also required to prevent renal toxicity, particularly if the plasma level exceeds 0.8 mmol/L.⁷ Because of lithium’s relatively narrow therapeutic index, its interaction with other medications, such as angiotensin-converting enzyme inhibitors, diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), and carbamazepine, can also precipitate lithium toxicity.⁸ We describe a lesson learned from a case of lithium toxicity in an otherwise healthy patient with bipolar disorder.

Case report

An otherwise healthy 39-year-old woman diagnosed with bipolar type I disorder was receiving valproate sodium 600 mg/d and olanzapine 10 mg/d. Despite improvement in her mood, she gained 11.6 kg following 6 months of treatment. As a result, olanzapine was switched to aripiprazole 10 mg/d that was later increased to 15 mg/d, and sodium valproate was gradually optimized up to 1,000 mg/d. She later complained of hair thinning and hair loss so she self-adjusted her medication dosages, which resulted in frequent relapses. Her mood stabilizer was changed from sodium valproate to lithium 600 mg/d.

Unfortunately, after taking lithium for 15 days, she returned to us with fever associated with reduced oral intake, poor sleep, bilateral upper limb rigidity, and bilateral hand tremor. She also complained of extreme thirst and fatigue but no vomiting or diarrhea. She had difficulty falling asleep and slept for only 1 to 2 hours a day. Her symptoms worsened when a general practitioner prescribed NSAIDs for her fever and body ache. Her tremors were later generalized, which made it difficult for her to take her oral medications and disturbed her speech and movement.

On evaluation, our patient appeared comfortable and not agitated. She was orientated to time, place, and person. Her blood pressure was 139/89 mmHg, heart rate was 104 bpm, and she was afebrile. She was dehydrated with minimal urine output. She had coarse tremor in her upper and lower limbs, which were hypertonic but did not display hyperreflexia or clonus. There was no nystagmus or ataxia. A mental state examination showed no signs of manic, hypomanic, or depressive symptoms. She had slurred speech, and her affect was restricted.

Blood investigation revealed a suprathreshold lithium level of 1.70 mmol/L (normal: 0.8 to 1.2 mmol/L). Biochemical parameters showed evidence of acute kidney injury (urea: 6.1 mmol/L; creatinine: 0.140 mmol/L), with no electrolyte imbalance. There was no evidence of hypothyroidism (thyroid-stimulating hormone: 14.9 mIU/L; free thyroxine: 9.9 pmol/L), hyperparathyroidism, or hypercalcemia. Autoimmune markers were positive for antinuclear antibody (titre 1:320) and anti-double stranded DNA (76.8 IU/mL). Apart from hair loss, she denied other symptoms associated with autoimmune disease, such as joint pain, butterfly rash, or persistent fatigue. Other routine blood investigations were within normal limits. Her urine protein throughout admission had shown persistent proteinuria ranging from 3+ to 4+. Electrocardiogram (ECG) showed normal sinus rhythm with no T wave inversion or QT prolongation.

Continue to: A detailed family history...

A detailed family history later confirmed a strong family history of renal disease: her mother had lupus nephritis with nephrotic syndrome, and her brother had died from complications of a rapidly progressive glomerulonephritis. Her renal function prior to lithium initiation was within normal limits (urea: 4.0 mmol/L; serum creatinine: 78 µmol/L).

In the ward, lithium and aripiprazole were discontinued, and she was hydrated. Combined care with the psychiatric and medical teams was established early to safeguard against potential CNS deterioration. She showed marked clinical improvement by Day 3, with the resolution of coarse tremor and rigidity as well as normalization of blood parameters. Her lithium level returned to a therapeutic level by Day 4 after lithium discontinuation, and her renal profile gradually normalized. She was restarted on aripiprazole 10 mg/d for her bipolar illness and responded well. She was discharged on Day 5 with a referral to the nephrology team for further intervention.

Lessons learned

This case highlights the issue of lithium safety in susceptible individuals and the importance of risk stratification in this group of patients. Lithium is an effective treatment for bipolar I disorder and has also been used as adjunctive treatment for major depressive disorder, schizoaffective disorder, treatment-resistant schizophrenia, anorexia nervosa and bulimia nervosa, and the control of chronic aggression.⁹ Lithium is completely absorbed by the gastrointestinal tract following ingestion, is not metabolized, and is eliminated almost entirely by the kidneys (though trace amounts may be found in feces and perspiration).

In our case, a detailed family history of renal disease was not adequately explored until our patient presented with signs suggestive of lithium toxicity. Our patient had been prescribed lithium 600 mg/d as a maintenance therapy. Upon starting lithium, her baseline biochemical parameters were within normal limits, and renal issues were not suspected. The hair thinning and hair loss she experienced could have been an adverse effect of valproate sodium or a manifestation of an underlying autoimmune disease. Coupled with the use of NSAIDs that could have precipitated acute kidney injury, her poor oral intake and dehydration during the acute illness further impaired lithium excretion, leading to a suprathreshold plasma level despite a low dose of lithium. Therefore, before prescribing lithium, a thorough medical and family history is needed, supplemented by an evaluation of renal function, serum electrolytes, and thyroid function to determine the starting dosage of lithium. Routine vital sign assessment and ECG should also be conducted, and concurrent medications and pregnancy status should be confirmed before prescribing lithium. Regular lithium level monitoring is essential.

Measuring a patient’s estimated glomerular filtration rate (eGFR) is recommended to validate renal status¹⁰ and classify and stage kidney disease.¹¹ Combining eGFR with blood urea nitrogen, serum creatinine, and urine microscopic analysis further improves the prediction of renal disease in early stages. We recommend considering a blood test for autoimmune markers in patients with clinical suspicion of autoimmune disease, in the presence of suggestive signs and symptoms, and/or in patients with a positive family history (Table).

Before starting lithium, in addition to conducting a detailed clinical evaluation, information about symptoms and the risk of lithium toxicity should be discussed with patients.¹² Our case serves as a timely reminder that the lack of suggestive biochemical parameters of renal disease should not rule out an underlying renal disease, and a strong family history of renal disease should warrant suspicion of a possible autoimmune origin.

We suggest that future studies evaluate the risks of lithium toxicity in susceptible groups of patients, such as those with family history of renal disease.

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 informa tion, contact [email protected].

Lithium carbonate is a mood stabilizer that is effective in the treatment of bipolar disorder, particularly in controlling mania.¹ Lithium can reduce the risk of suicide,² treat aggression and self-mutilating behavior,³ and prevent steroid-induced psychosis.⁴ It also can raise the white cell count in patients with clozapine-induced leukopenia.⁵

To prevent or lower the risk of relapse, the therapeutic plasma level of lithium should be regularly monitored to ensure an optimal concentration in the CNS. The highest tolerable level of lithium in the plasma is 0.6 to 0.8 mmol/L, with the optimal level ranging up to 1.2 mmol/L.⁶ Regular monitoring of renal function is also required to prevent renal toxicity, particularly if the plasma level exceeds 0.8 mmol/L.⁷ Because of lithium’s relatively narrow therapeutic index, its interaction with other medications, such as angiotensin-converting enzyme inhibitors, diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), and carbamazepine, can also precipitate lithium toxicity.⁸ We describe a lesson learned from a case of lithium toxicity in an otherwise healthy patient with bipolar disorder.

Case report

An otherwise healthy 39-year-old woman diagnosed with bipolar type I disorder was receiving valproate sodium 600 mg/d and olanzapine 10 mg/d. Despite improvement in her mood, she gained 11.6 kg following 6 months of treatment. As a result, olanzapine was switched to aripiprazole 10 mg/d that was later increased to 15 mg/d, and sodium valproate was gradually optimized up to 1,000 mg/d. She later complained of hair thinning and hair loss so she self-adjusted her medication dosages, which resulted in frequent relapses. Her mood stabilizer was changed from sodium valproate to lithium 600 mg/d.

Unfortunately, after taking lithium for 15 days, she returned to us with fever associated with reduced oral intake, poor sleep, bilateral upper limb rigidity, and bilateral hand tremor. She also complained of extreme thirst and fatigue but no vomiting or diarrhea. She had difficulty falling asleep and slept for only 1 to 2 hours a day. Her symptoms worsened when a general practitioner prescribed NSAIDs for her fever and body ache. Her tremors were later generalized, which made it difficult for her to take her oral medications and disturbed her speech and movement.

On evaluation, our patient appeared comfortable and not agitated. She was orientated to time, place, and person. Her blood pressure was 139/89 mmHg, heart rate was 104 bpm, and she was afebrile. She was dehydrated with minimal urine output. She had coarse tremor in her upper and lower limbs, which were hypertonic but did not display hyperreflexia or clonus. There was no nystagmus or ataxia. A mental state examination showed no signs of manic, hypomanic, or depressive symptoms. She had slurred speech, and her affect was restricted.

Blood investigation revealed a suprathreshold lithium level of 1.70 mmol/L (normal: 0.8 to 1.2 mmol/L). Biochemical parameters showed evidence of acute kidney injury (urea: 6.1 mmol/L; creatinine: 0.140 mmol/L), with no electrolyte imbalance. There was no evidence of hypothyroidism (thyroid-stimulating hormone: 14.9 mIU/L; free thyroxine: 9.9 pmol/L), hyperparathyroidism, or hypercalcemia. Autoimmune markers were positive for antinuclear antibody (titre 1:320) and anti-double stranded DNA (76.8 IU/mL). Apart from hair loss, she denied other symptoms associated with autoimmune disease, such as joint pain, butterfly rash, or persistent fatigue. Other routine blood investigations were within normal limits. Her urine protein throughout admission had shown persistent proteinuria ranging from 3+ to 4+. Electrocardiogram (ECG) showed normal sinus rhythm with no T wave inversion or QT prolongation.

Continue to: A detailed family history...

A detailed family history later confirmed a strong family history of renal disease: her mother had lupus nephritis with nephrotic syndrome, and her brother had died from complications of a rapidly progressive glomerulonephritis. Her renal function prior to lithium initiation was within normal limits (urea: 4.0 mmol/L; serum creatinine: 78 µmol/L).

In the ward, lithium and aripiprazole were discontinued, and she was hydrated. Combined care with the psychiatric and medical teams was established early to safeguard against potential CNS deterioration. She showed marked clinical improvement by Day 3, with the resolution of coarse tremor and rigidity as well as normalization of blood parameters. Her lithium level returned to a therapeutic level by Day 4 after lithium discontinuation, and her renal profile gradually normalized. She was restarted on aripiprazole 10 mg/d for her bipolar illness and responded well. She was discharged on Day 5 with a referral to the nephrology team for further intervention.

Lessons learned

This case highlights the issue of lithium safety in susceptible individuals and the importance of risk stratification in this group of patients. Lithium is an effective treatment for bipolar I disorder and has also been used as adjunctive treatment for major depressive disorder, schizoaffective disorder, treatment-resistant schizophrenia, anorexia nervosa and bulimia nervosa, and the control of chronic aggression.⁹ Lithium is completely absorbed by the gastrointestinal tract following ingestion, is not metabolized, and is eliminated almost entirely by the kidneys (though trace amounts may be found in feces and perspiration).

In our case, a detailed family history of renal disease was not adequately explored until our patient presented with signs suggestive of lithium toxicity. Our patient had been prescribed lithium 600 mg/d as a maintenance therapy. Upon starting lithium, her baseline biochemical parameters were within normal limits, and renal issues were not suspected. The hair thinning and hair loss she experienced could have been an adverse effect of valproate sodium or a manifestation of an underlying autoimmune disease. Coupled with the use of NSAIDs that could have precipitated acute kidney injury, her poor oral intake and dehydration during the acute illness further impaired lithium excretion, leading to a suprathreshold plasma level despite a low dose of lithium. Therefore, before prescribing lithium, a thorough medical and family history is needed, supplemented by an evaluation of renal function, serum electrolytes, and thyroid function to determine the starting dosage of lithium. Routine vital sign assessment and ECG should also be conducted, and concurrent medications and pregnancy status should be confirmed before prescribing lithium. Regular lithium level monitoring is essential.

Measuring a patient’s estimated glomerular filtration rate (eGFR) is recommended to validate renal status¹⁰ and classify and stage kidney disease.¹¹ Combining eGFR with blood urea nitrogen, serum creatinine, and urine microscopic analysis further improves the prediction of renal disease in early stages. We recommend considering a blood test for autoimmune markers in patients with clinical suspicion of autoimmune disease, in the presence of suggestive signs and symptoms, and/or in patients with a positive family history (Table).

Before starting lithium, in addition to conducting a detailed clinical evaluation, information about symptoms and the risk of lithium toxicity should be discussed with patients.¹² Our case serves as a timely reminder that the lack of suggestive biochemical parameters of renal disease should not rule out an underlying renal disease, and a strong family history of renal disease should warrant suspicion of a possible autoimmune origin.

We suggest that future studies evaluate the risks of lithium toxicity in susceptible groups of patients, such as those with family history of renal disease.

CASE Depressed, anxious, and suicidal

Mr. J, age 72, is brought to the emergency department by law enforcement at his wife’s request due to worsening suicidal thoughts and anxiety. He has a history of major depressive disorder (MDD) and chronic kidney disease (CKD). Mr. J has been compliant with his medications, but they seem to no longer be effective. He is admitted to the geriatric psychiatry unit.

HISTORY Increased debilitation

Over the past several years, Mr. J has experienced increasing debilitation at home, including difficulty walking and an inability to perform activities of daily life. Recently, he has begun to ask for multiple pills in an attempt to take his own life.

Mr. J has been previously treated in a psychiatric clinic with duloxetine 60 mg/d, mirtazapine 30 mg/d at bedtime, buspirone 15 mg 3 times a day, and trazodone 50 mg/d at bedtime. He is also taking amlodipine 5 mg twice daily for hypertension, lisinopril 2.5 mg/d for hypertension, furosemide 20 mg/d orally for CKD, and potassium chloride 10 mEq/d for hypokalemia secondary to CKD and furosemide use. Over the past year, his psychiatric medications have been steadily increased to target his MDD and anxiety.

EVALUATION Disorientation and Stage 3A CKD

In the psychiatric unit, Mr. J describes panic, feelings of impending doom, and profound anxiety. He states he has increasing anxiety related to “being a burden” on his family and wife. Additionally, he describes decreased appetite, difficulty sleeping, low energy, difficulty concentrating, no interest in outside activities, and feelings of hopelessness.

Mr. J’s temperature is 39.2^o C; heart rate is 109 beats per minute; respiratory rate is 18 breaths per minute; blood pressure is 157/83 mm Hg; and pulse oximetry is 97%. Laboratory screening indicates a red blood cell count of 3.57, hemoglobin 11.2, hematocrit 33.8, red blood cell distribution width 17.5, blood urea nitrogen 45, creatinine 1.5 with no known baseline, and an estimated glomerular filtration rate (GFR) of 46 mL/min, indicating Stage 3A CKD (Table 1¹). Additional testing rules out other potential causes of delirium and psychosis.

A physical exam reveals Mr. J has a fine tremor, myoclonus, muscle rigidity, and hyperreflexia. He is oriented to name, but not to date, place, or situation, and is easily confused. Mr. J uses a walker but has significant tremors while walking and immediately asks for assistance due to profound anxiety related to a fear of falling. Mr. J’s mood and affect are labile with tearful and anxious episodes. His anxiety focuses on overvalued thoughts of minor or irrelevant concerns. Additionally, he has poor insight and judgment. When asked about the cause of his anxiety, Mr. J says, “I don’t know why I’m anxious; I’m just a worrywart.” His memory is impaired, and he does not know why he is in the hospital. Mr. J scores 24 on the Montreal Cognitive Assessment, which indicates mild impairment.

Mr. J continues to endorse suicidal ideation but denies homicidal thoughts. Based on these symptoms, the differential diagnosis includes serotonin syndrome, MDD with suicidal ideation, generalized anxiety disorder, and panic disorder.

Continue to: The authors' observations

[polldaddy:11273789]

The authors’ observations

GFR is used to determine the level of renal impairment. Mr. J’s GFR of 46 mL/min indicates Stage 3A CKD (Table 1¹ ). Additionally, he displayed anemia and increased creatinine due to CKD. Twenty percent of patients with CKD also experience MDD.² In a prospective observational cohort study, Hedayati et al³ found that Stage 2 to Stage 5 CKD with MDD leads to an increased risk of death, hospitalization, or progression to dialysis. It is important to properly manage Mr. J’s MDD and CKD to prevent future comorbidities. Renal impairment is common in people age >65.⁴ Even when GFR is normal, it is recommended to decrease dosing of medications in older adults due to age-related decreased renal excretion. As kidneys decrease in function, their ability to excrete normal amounts of medications also decreases, leading to increased serum levels and potential toxicity.

A combination of 4 serotonergic psychotropic medications may not be unusual to address treatment-resistant depression in a healthy, nongeriatric adult. However, Mr. J displayed signs of serotonin toxicity, such as hyperthermia, tachycardia, increased blood pressure, increased tremors, myoclonus, hyperreflexia, and muscle rigidity. These are classic signs of serotonin toxicity. For Mr. J, serotonin toxicity can be treated with the removal of serotonergic medications and lorazepam for symptom relief. If symptoms persist, cyproheptadine, a serotonin antagonist, can be used. Mr. J’s psychotropic medications were increased in an outpatient setting and he was unable to renally excrete higher doses of these serotonergic agents, which lead to chronic serotonin toxicity.

It is important to rule out other causes of psychosis or delirium in geriatric patients. A study by Marcantonio et al⁵ found that >40% of patients referred to a consulting psychiatrist for depression ultimately had delirium, and this was more likely in geriatric patients.

TREATMENT Adjustments to the medication regimen

The treatment team decides to taper and discontinue duloxetine, buspirone, and trazodone and reduce mirtazapine to 15 mg/d at bedtime. Additionally, oral lorazepam 1 mg as needed is prescribed to alleviate agitation and correct vital signs. Mr. J’s vital signs improve, with decreased temperature and normal cardiac and respiratory rhythms.

Mr. J’s Stage 3A CKD is treated with oral fluids, and his hypertension is managed with an increase of lisinopril from 2.5 mg/d to 10 mg/d. After 10 days on the psychiatric unit, he shows improvement, decreased anxiety, and remission of suicidal ideation.

Continue to: The authors' observations

[polldaddy:11273790]

The authors’ observations

In 2019, the American Geriatric Society (AGS) updated the Beers Criteria for potentially inappropriate medication use in older adults.⁴ The Beers Criteria were created to educate clinicians about the use of potentially inappropriate medications that have an unfavorable balance of benefits and risks compared to alternative treatments. The AGS lists medications that should be avoided or have their dosage reduced with varying levels of kidney function in older adults. Duloxetine is one of the medications listed with the recommendation to avoid for patients with a creatinine clearance <30 mL/min. Creatinine clearance is an estimation of GFR.

Although duloxetine is mentioned in the Beers Criteria, many other antidepressants have metabolites excreted by the kidneys.⁶ Potential adverse effects include increased bleeding, nausea, vomiting, and serotonin toxicity symptoms.⁷ Mr. J has Stage 3A CKD and takes 4 psychotropics, which will additively increase the serum concentration of serotonergic medications. In terms of treatment for serotonin toxicity, it is important to remove the causative medications. After discontinuing serotonergic medications, lorazepam can be administered as needed. If a patient continues to have symptoms, cyproheptadine is an option.

For patients with impaired renal function, adding nonpharmacologic options should be considered, such as cognitive-behavioral therapy, electroconvulsive therapy, and transcranial magnetic stimulation. Table 2^4,8-18 lists the minimum effective doses for well-known medications for treating MDD.

OUTCOME Improvement and discharge

Mr. J’s confusion improves, his heart rate decreases, and his feelings of panic and doom improve. He continues to have depressive symptoms, but his suicidal ideation stops. At discharge, Mr. J is receiving mirtazapine 15 mg/d, potassium chloride 10 mEq/d orally, lisinopril 20 mg/d orally at bedtime, furosemide 20 mg/d orally, and amlodipine 5 mg orally twice a day. Additionally, the treatment team recommends psychotherapy to Mr. J to address his anxiety and depression.

Bottom Line

Older patients are more sensitive to psychotropic medications, regardless of any comorbidities. It is important to review each patient’s glomerular filtration rate to better understand their renal function and adjust medications accordingly.

Related Resources

• Whittaker P, Vordenberg SE, Coe AB. Deprescribing in older adults: an overview. Current Psychiatry. 2022;21(5):40-43. doi:10.12788/cp.0246
• Gibson G, Kennedy LH, Barlow G. Polypharmacy in older adults. Current Psychiatry. 2020;19(4):40-46.
• Barr R, Miskle B, Thomas C. Management of major depressive disorder with psychotic features. Current Psychiatry. 2021;20(2):30-33. doi:10.12788/cp.0092

Drug Brand Names

Amlodipine • Norvasc
Buspirone • BuSpar
Citalopram • Celexa
Cyproheptadine • Periactin
Desvenlafaxine • Pristiq
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
Furosemide • Lasix
Lisinopril • Zestril
Lorazepam • Ativan
Mirtazapine • Remeron
Paroxetine • Paxil
Sertraline • Zoloft
Trazodone • Desyrel
Venlafaxine • Effexor

CASE Depressed, anxious, and suicidal

Mr. J, age 72, is brought to the emergency department by law enforcement at his wife’s request due to worsening suicidal thoughts and anxiety. He has a history of major depressive disorder (MDD) and chronic kidney disease (CKD). Mr. J has been compliant with his medications, but they seem to no longer be effective. He is admitted to the geriatric psychiatry unit.

HISTORY Increased debilitation

Over the past several years, Mr. J has experienced increasing debilitation at home, including difficulty walking and an inability to perform activities of daily life. Recently, he has begun to ask for multiple pills in an attempt to take his own life.

Mr. J has been previously treated in a psychiatric clinic with duloxetine 60 mg/d, mirtazapine 30 mg/d at bedtime, buspirone 15 mg 3 times a day, and trazodone 50 mg/d at bedtime. He is also taking amlodipine 5 mg twice daily for hypertension, lisinopril 2.5 mg/d for hypertension, furosemide 20 mg/d orally for CKD, and potassium chloride 10 mEq/d for hypokalemia secondary to CKD and furosemide use. Over the past year, his psychiatric medications have been steadily increased to target his MDD and anxiety.

EVALUATION Disorientation and Stage 3A CKD

In the psychiatric unit, Mr. J describes panic, feelings of impending doom, and profound anxiety. He states he has increasing anxiety related to “being a burden” on his family and wife. Additionally, he describes decreased appetite, difficulty sleeping, low energy, difficulty concentrating, no interest in outside activities, and feelings of hopelessness.

Mr. J’s temperature is 39.2^o C; heart rate is 109 beats per minute; respiratory rate is 18 breaths per minute; blood pressure is 157/83 mm Hg; and pulse oximetry is 97%. Laboratory screening indicates a red blood cell count of 3.57, hemoglobin 11.2, hematocrit 33.8, red blood cell distribution width 17.5, blood urea nitrogen 45, creatinine 1.5 with no known baseline, and an estimated glomerular filtration rate (GFR) of 46 mL/min, indicating Stage 3A CKD (Table 1¹). Additional testing rules out other potential causes of delirium and psychosis.

A physical exam reveals Mr. J has a fine tremor, myoclonus, muscle rigidity, and hyperreflexia. He is oriented to name, but not to date, place, or situation, and is easily confused. Mr. J uses a walker but has significant tremors while walking and immediately asks for assistance due to profound anxiety related to a fear of falling. Mr. J’s mood and affect are labile with tearful and anxious episodes. His anxiety focuses on overvalued thoughts of minor or irrelevant concerns. Additionally, he has poor insight and judgment. When asked about the cause of his anxiety, Mr. J says, “I don’t know why I’m anxious; I’m just a worrywart.” His memory is impaired, and he does not know why he is in the hospital. Mr. J scores 24 on the Montreal Cognitive Assessment, which indicates mild impairment.

Mr. J continues to endorse suicidal ideation but denies homicidal thoughts. Based on these symptoms, the differential diagnosis includes serotonin syndrome, MDD with suicidal ideation, generalized anxiety disorder, and panic disorder.

Continue to: The authors' observations

[polldaddy:11273789]

The authors’ observations

GFR is used to determine the level of renal impairment. Mr. J’s GFR of 46 mL/min indicates Stage 3A CKD (Table 1¹ ). Additionally, he displayed anemia and increased creatinine due to CKD. Twenty percent of patients with CKD also experience MDD.² In a prospective observational cohort study, Hedayati et al³ found that Stage 2 to Stage 5 CKD with MDD leads to an increased risk of death, hospitalization, or progression to dialysis. It is important to properly manage Mr. J’s MDD and CKD to prevent future comorbidities. Renal impairment is common in people age >65.⁴ Even when GFR is normal, it is recommended to decrease dosing of medications in older adults due to age-related decreased renal excretion. As kidneys decrease in function, their ability to excrete normal amounts of medications also decreases, leading to increased serum levels and potential toxicity.

A combination of 4 serotonergic psychotropic medications may not be unusual to address treatment-resistant depression in a healthy, nongeriatric adult. However, Mr. J displayed signs of serotonin toxicity, such as hyperthermia, tachycardia, increased blood pressure, increased tremors, myoclonus, hyperreflexia, and muscle rigidity. These are classic signs of serotonin toxicity. For Mr. J, serotonin toxicity can be treated with the removal of serotonergic medications and lorazepam for symptom relief. If symptoms persist, cyproheptadine, a serotonin antagonist, can be used. Mr. J’s psychotropic medications were increased in an outpatient setting and he was unable to renally excrete higher doses of these serotonergic agents, which lead to chronic serotonin toxicity.

It is important to rule out other causes of psychosis or delirium in geriatric patients. A study by Marcantonio et al⁵ found that >40% of patients referred to a consulting psychiatrist for depression ultimately had delirium, and this was more likely in geriatric patients.

TREATMENT Adjustments to the medication regimen

The treatment team decides to taper and discontinue duloxetine, buspirone, and trazodone and reduce mirtazapine to 15 mg/d at bedtime. Additionally, oral lorazepam 1 mg as needed is prescribed to alleviate agitation and correct vital signs. Mr. J’s vital signs improve, with decreased temperature and normal cardiac and respiratory rhythms.

Mr. J’s Stage 3A CKD is treated with oral fluids, and his hypertension is managed with an increase of lisinopril from 2.5 mg/d to 10 mg/d. After 10 days on the psychiatric unit, he shows improvement, decreased anxiety, and remission of suicidal ideation.

Continue to: The authors' observations

[polldaddy:11273790]

The authors’ observations

In 2019, the American Geriatric Society (AGS) updated the Beers Criteria for potentially inappropriate medication use in older adults.⁴ The Beers Criteria were created to educate clinicians about the use of potentially inappropriate medications that have an unfavorable balance of benefits and risks compared to alternative treatments. The AGS lists medications that should be avoided or have their dosage reduced with varying levels of kidney function in older adults. Duloxetine is one of the medications listed with the recommendation to avoid for patients with a creatinine clearance <30 mL/min. Creatinine clearance is an estimation of GFR.

Although duloxetine is mentioned in the Beers Criteria, many other antidepressants have metabolites excreted by the kidneys.⁶ Potential adverse effects include increased bleeding, nausea, vomiting, and serotonin toxicity symptoms.⁷ Mr. J has Stage 3A CKD and takes 4 psychotropics, which will additively increase the serum concentration of serotonergic medications. In terms of treatment for serotonin toxicity, it is important to remove the causative medications. After discontinuing serotonergic medications, lorazepam can be administered as needed. If a patient continues to have symptoms, cyproheptadine is an option.

For patients with impaired renal function, adding nonpharmacologic options should be considered, such as cognitive-behavioral therapy, electroconvulsive therapy, and transcranial magnetic stimulation. Table 2^4,8-18 lists the minimum effective doses for well-known medications for treating MDD.

OUTCOME Improvement and discharge

Mr. J’s confusion improves, his heart rate decreases, and his feelings of panic and doom improve. He continues to have depressive symptoms, but his suicidal ideation stops. At discharge, Mr. J is receiving mirtazapine 15 mg/d, potassium chloride 10 mEq/d orally, lisinopril 20 mg/d orally at bedtime, furosemide 20 mg/d orally, and amlodipine 5 mg orally twice a day. Additionally, the treatment team recommends psychotherapy to Mr. J to address his anxiety and depression.

Bottom Line

Older patients are more sensitive to psychotropic medications, regardless of any comorbidities. It is important to review each patient’s glomerular filtration rate to better understand their renal function and adjust medications accordingly.

Related Resources

• Whittaker P, Vordenberg SE, Coe AB. Deprescribing in older adults: an overview. Current Psychiatry. 2022;21(5):40-43. doi:10.12788/cp.0246
• Gibson G, Kennedy LH, Barlow G. Polypharmacy in older adults. Current Psychiatry. 2020;19(4):40-46.
• Barr R, Miskle B, Thomas C. Management of major depressive disorder with psychotic features. Current Psychiatry. 2021;20(2):30-33. doi:10.12788/cp.0092

Drug Brand Names

Amlodipine • Norvasc
Buspirone • BuSpar
Citalopram • Celexa
Cyproheptadine • Periactin
Desvenlafaxine • Pristiq
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
Furosemide • Lasix
Lisinopril • Zestril
Lorazepam • Ativan
Mirtazapine • Remeron
Paroxetine • Paxil
Sertraline • Zoloft
Trazodone • Desyrel
Venlafaxine • Effexor

CASE Depressed, anxious, and suicidal

Mr. J, age 72, is brought to the emergency department by law enforcement at his wife’s request due to worsening suicidal thoughts and anxiety. He has a history of major depressive disorder (MDD) and chronic kidney disease (CKD). Mr. J has been compliant with his medications, but they seem to no longer be effective. He is admitted to the geriatric psychiatry unit.

HISTORY Increased debilitation

Over the past several years, Mr. J has experienced increasing debilitation at home, including difficulty walking and an inability to perform activities of daily life. Recently, he has begun to ask for multiple pills in an attempt to take his own life.

Mr. J has been previously treated in a psychiatric clinic with duloxetine 60 mg/d, mirtazapine 30 mg/d at bedtime, buspirone 15 mg 3 times a day, and trazodone 50 mg/d at bedtime. He is also taking amlodipine 5 mg twice daily for hypertension, lisinopril 2.5 mg/d for hypertension, furosemide 20 mg/d orally for CKD, and potassium chloride 10 mEq/d for hypokalemia secondary to CKD and furosemide use. Over the past year, his psychiatric medications have been steadily increased to target his MDD and anxiety.

EVALUATION Disorientation and Stage 3A CKD

In the psychiatric unit, Mr. J describes panic, feelings of impending doom, and profound anxiety. He states he has increasing anxiety related to “being a burden” on his family and wife. Additionally, he describes decreased appetite, difficulty sleeping, low energy, difficulty concentrating, no interest in outside activities, and feelings of hopelessness.

Mr. J’s temperature is 39.2^o C; heart rate is 109 beats per minute; respiratory rate is 18 breaths per minute; blood pressure is 157/83 mm Hg; and pulse oximetry is 97%. Laboratory screening indicates a red blood cell count of 3.57, hemoglobin 11.2, hematocrit 33.8, red blood cell distribution width 17.5, blood urea nitrogen 45, creatinine 1.5 with no known baseline, and an estimated glomerular filtration rate (GFR) of 46 mL/min, indicating Stage 3A CKD (Table 1¹). Additional testing rules out other potential causes of delirium and psychosis.

A physical exam reveals Mr. J has a fine tremor, myoclonus, muscle rigidity, and hyperreflexia. He is oriented to name, but not to date, place, or situation, and is easily confused. Mr. J uses a walker but has significant tremors while walking and immediately asks for assistance due to profound anxiety related to a fear of falling. Mr. J’s mood and affect are labile with tearful and anxious episodes. His anxiety focuses on overvalued thoughts of minor or irrelevant concerns. Additionally, he has poor insight and judgment. When asked about the cause of his anxiety, Mr. J says, “I don’t know why I’m anxious; I’m just a worrywart.” His memory is impaired, and he does not know why he is in the hospital. Mr. J scores 24 on the Montreal Cognitive Assessment, which indicates mild impairment.

Mr. J continues to endorse suicidal ideation but denies homicidal thoughts. Based on these symptoms, the differential diagnosis includes serotonin syndrome, MDD with suicidal ideation, generalized anxiety disorder, and panic disorder.

Continue to: The authors' observations

[polldaddy:11273789]

The authors’ observations

GFR is used to determine the level of renal impairment. Mr. J’s GFR of 46 mL/min indicates Stage 3A CKD (Table 1¹ ). Additionally, he displayed anemia and increased creatinine due to CKD. Twenty percent of patients with CKD also experience MDD.² In a prospective observational cohort study, Hedayati et al³ found that Stage 2 to Stage 5 CKD with MDD leads to an increased risk of death, hospitalization, or progression to dialysis. It is important to properly manage Mr. J’s MDD and CKD to prevent future comorbidities. Renal impairment is common in people age >65.⁴ Even when GFR is normal, it is recommended to decrease dosing of medications in older adults due to age-related decreased renal excretion. As kidneys decrease in function, their ability to excrete normal amounts of medications also decreases, leading to increased serum levels and potential toxicity.

A combination of 4 serotonergic psychotropic medications may not be unusual to address treatment-resistant depression in a healthy, nongeriatric adult. However, Mr. J displayed signs of serotonin toxicity, such as hyperthermia, tachycardia, increased blood pressure, increased tremors, myoclonus, hyperreflexia, and muscle rigidity. These are classic signs of serotonin toxicity. For Mr. J, serotonin toxicity can be treated with the removal of serotonergic medications and lorazepam for symptom relief. If symptoms persist, cyproheptadine, a serotonin antagonist, can be used. Mr. J’s psychotropic medications were increased in an outpatient setting and he was unable to renally excrete higher doses of these serotonergic agents, which lead to chronic serotonin toxicity.

It is important to rule out other causes of psychosis or delirium in geriatric patients. A study by Marcantonio et al⁵ found that >40% of patients referred to a consulting psychiatrist for depression ultimately had delirium, and this was more likely in geriatric patients.

TREATMENT Adjustments to the medication regimen

The treatment team decides to taper and discontinue duloxetine, buspirone, and trazodone and reduce mirtazapine to 15 mg/d at bedtime. Additionally, oral lorazepam 1 mg as needed is prescribed to alleviate agitation and correct vital signs. Mr. J’s vital signs improve, with decreased temperature and normal cardiac and respiratory rhythms.

Mr. J’s Stage 3A CKD is treated with oral fluids, and his hypertension is managed with an increase of lisinopril from 2.5 mg/d to 10 mg/d. After 10 days on the psychiatric unit, he shows improvement, decreased anxiety, and remission of suicidal ideation.

Continue to: The authors' observations

[polldaddy:11273790]

The authors’ observations

In 2019, the American Geriatric Society (AGS) updated the Beers Criteria for potentially inappropriate medication use in older adults.⁴ The Beers Criteria were created to educate clinicians about the use of potentially inappropriate medications that have an unfavorable balance of benefits and risks compared to alternative treatments. The AGS lists medications that should be avoided or have their dosage reduced with varying levels of kidney function in older adults. Duloxetine is one of the medications listed with the recommendation to avoid for patients with a creatinine clearance <30 mL/min. Creatinine clearance is an estimation of GFR.

Although duloxetine is mentioned in the Beers Criteria, many other antidepressants have metabolites excreted by the kidneys.⁶ Potential adverse effects include increased bleeding, nausea, vomiting, and serotonin toxicity symptoms.⁷ Mr. J has Stage 3A CKD and takes 4 psychotropics, which will additively increase the serum concentration of serotonergic medications. In terms of treatment for serotonin toxicity, it is important to remove the causative medications. After discontinuing serotonergic medications, lorazepam can be administered as needed. If a patient continues to have symptoms, cyproheptadine is an option.

For patients with impaired renal function, adding nonpharmacologic options should be considered, such as cognitive-behavioral therapy, electroconvulsive therapy, and transcranial magnetic stimulation. Table 2^4,8-18 lists the minimum effective doses for well-known medications for treating MDD.

OUTCOME Improvement and discharge

Mr. J’s confusion improves, his heart rate decreases, and his feelings of panic and doom improve. He continues to have depressive symptoms, but his suicidal ideation stops. At discharge, Mr. J is receiving mirtazapine 15 mg/d, potassium chloride 10 mEq/d orally, lisinopril 20 mg/d orally at bedtime, furosemide 20 mg/d orally, and amlodipine 5 mg orally twice a day. Additionally, the treatment team recommends psychotherapy to Mr. J to address his anxiety and depression.

Bottom Line

Older patients are more sensitive to psychotropic medications, regardless of any comorbidities. It is important to review each patient’s glomerular filtration rate to better understand their renal function and adjust medications accordingly.

Related Resources

• Whittaker P, Vordenberg SE, Coe AB. Deprescribing in older adults: an overview. Current Psychiatry. 2022;21(5):40-43. doi:10.12788/cp.0246
• Gibson G, Kennedy LH, Barlow G. Polypharmacy in older adults. Current Psychiatry. 2020;19(4):40-46.
• Barr R, Miskle B, Thomas C. Management of major depressive disorder with psychotic features. Current Psychiatry. 2021;20(2):30-33. doi:10.12788/cp.0092

Drug Brand Names

Amlodipine • Norvasc
Buspirone • BuSpar
Citalopram • Celexa
Cyproheptadine • Periactin
Desvenlafaxine • Pristiq
Duloxetine • Cymbalta
Escitalopram • Lexapro
Fluoxetine • Prozac
Furosemide • Lasix
Lisinopril • Zestril
Lorazepam • Ativan
Mirtazapine • Remeron
Paroxetine • Paxil
Sertraline • Zoloft
Trazodone • Desyrel
Venlafaxine • Effexor