Article

Practice Gap

Pain and anxiety are common in fully conscious patients undergoing dermatologic surgery with local anesthesia. Particularly during nail surgery, pain from anesthetic injection—caused by both needle insertion and fluid infiltration—occurs because the nail unit is highly vascularized and innervated.¹ Current methods to improve patient comfort during infiltration include use of a buffered anesthetic solution, warming the anesthetic, slower technique, and direct cold application.²

Perioperative anxiety correlates with increased postoperative pain, analgesic use, and delayed recovery. Furthermore, increased perioperative anxiety reduces the pain threshold and elevates estimates of pain intensity.³ Therefore, reducing procedure-related anxiety and pain may improve quality of care and ease patient discomfort.

Distraction is a common and practical nonpharmacotherapeutic technique for reducing pain and anxiety during medical procedures. The refocusing method of distraction aims to divert attention away from pain to more pleasant stimuli to reduce pain perception.³ Several methods of distraction—using stress balls, engaging in conversation, hand-holding, applying virtual reality, and playing videos—can decrease perioperative anxiety and pain.^3-6

Procedural pain and distraction techniques have been evaluated in the pediatric population more than in adults.⁴ Nail surgery–associated pain and distraction techniques for nail surgery have been inadequately studied.⁷

We offer a distraction technique utilizing a portable massager to ensure that patients are as comfortable as possible when the local anesthetic is injected prior to the first incision.

The Technique

A portable shiatsu massager that uses heat and deep-tissue kneading is placed on the upper thigh for toenail cases or lower arm for fingernail cases during injection of anesthetic to divert the patient’s attention from the surgical site (Figure). Kneading from the massage helps distract the patient from pain by introducing a competing, more pleasant, vibrating sensation that overrides pain signals; the relaxation component helps to diminish patient anxiety during injection.

Practice Implications

Use of a portable massager may reduce pain through both distraction and vibration. In a randomized clinical trial of 115 patients undergoing hand or facial surgery, patients who viewed a distraction video during the procedure reported a lower pain score compared to the control group (mean [SD] visual analog scale of pain score, 3.4 [2.6] vs 4.5 [2.6][P=.01]).⁴ In another randomized clinical trial of 25 patients undergoing lip augmentation, 92% of patients (23/25) in the vibration-assisted arm endorsed less pain during procedures compared to the arm without vibration (mean [SD] pain score, 3.82 [1.73] vs 5.6 [1.76][P<.001]).⁸

Utilization of a portable massager is a safe means of improving the patient experience; the distracting and relaxing effects and intense pulsations simultaneously reduce anxiety and pain during nail surgery. Controlled clinical trials are needed to evaluate its efficacy in diminishing both anxiety and pain during nail procedures compared to other analgesic methods.

Practice Gap

Pain and anxiety are common in fully conscious patients undergoing dermatologic surgery with local anesthesia. Particularly during nail surgery, pain from anesthetic injection—caused by both needle insertion and fluid infiltration—occurs because the nail unit is highly vascularized and innervated.¹ Current methods to improve patient comfort during infiltration include use of a buffered anesthetic solution, warming the anesthetic, slower technique, and direct cold application.²

Perioperative anxiety correlates with increased postoperative pain, analgesic use, and delayed recovery. Furthermore, increased perioperative anxiety reduces the pain threshold and elevates estimates of pain intensity.³ Therefore, reducing procedure-related anxiety and pain may improve quality of care and ease patient discomfort.

Distraction is a common and practical nonpharmacotherapeutic technique for reducing pain and anxiety during medical procedures. The refocusing method of distraction aims to divert attention away from pain to more pleasant stimuli to reduce pain perception.³ Several methods of distraction—using stress balls, engaging in conversation, hand-holding, applying virtual reality, and playing videos—can decrease perioperative anxiety and pain.^3-6

Procedural pain and distraction techniques have been evaluated in the pediatric population more than in adults.⁴ Nail surgery–associated pain and distraction techniques for nail surgery have been inadequately studied.⁷

We offer a distraction technique utilizing a portable massager to ensure that patients are as comfortable as possible when the local anesthetic is injected prior to the first incision.

The Technique

A portable shiatsu massager that uses heat and deep-tissue kneading is placed on the upper thigh for toenail cases or lower arm for fingernail cases during injection of anesthetic to divert the patient’s attention from the surgical site (Figure). Kneading from the massage helps distract the patient from pain by introducing a competing, more pleasant, vibrating sensation that overrides pain signals; the relaxation component helps to diminish patient anxiety during injection.

Practice Implications

Use of a portable massager may reduce pain through both distraction and vibration. In a randomized clinical trial of 115 patients undergoing hand or facial surgery, patients who viewed a distraction video during the procedure reported a lower pain score compared to the control group (mean [SD] visual analog scale of pain score, 3.4 [2.6] vs 4.5 [2.6][P=.01]).⁴ In another randomized clinical trial of 25 patients undergoing lip augmentation, 92% of patients (23/25) in the vibration-assisted arm endorsed less pain during procedures compared to the arm without vibration (mean [SD] pain score, 3.82 [1.73] vs 5.6 [1.76][P<.001]).⁸

Utilization of a portable massager is a safe means of improving the patient experience; the distracting and relaxing effects and intense pulsations simultaneously reduce anxiety and pain during nail surgery. Controlled clinical trials are needed to evaluate its efficacy in diminishing both anxiety and pain during nail procedures compared to other analgesic methods.

Practice Gap

Pain and anxiety are common in fully conscious patients undergoing dermatologic surgery with local anesthesia. Particularly during nail surgery, pain from anesthetic injection—caused by both needle insertion and fluid infiltration—occurs because the nail unit is highly vascularized and innervated.¹ Current methods to improve patient comfort during infiltration include use of a buffered anesthetic solution, warming the anesthetic, slower technique, and direct cold application.²

Perioperative anxiety correlates with increased postoperative pain, analgesic use, and delayed recovery. Furthermore, increased perioperative anxiety reduces the pain threshold and elevates estimates of pain intensity.³ Therefore, reducing procedure-related anxiety and pain may improve quality of care and ease patient discomfort.

Distraction is a common and practical nonpharmacotherapeutic technique for reducing pain and anxiety during medical procedures. The refocusing method of distraction aims to divert attention away from pain to more pleasant stimuli to reduce pain perception.³ Several methods of distraction—using stress balls, engaging in conversation, hand-holding, applying virtual reality, and playing videos—can decrease perioperative anxiety and pain.^3-6

Procedural pain and distraction techniques have been evaluated in the pediatric population more than in adults.⁴ Nail surgery–associated pain and distraction techniques for nail surgery have been inadequately studied.⁷

We offer a distraction technique utilizing a portable massager to ensure that patients are as comfortable as possible when the local anesthetic is injected prior to the first incision.

The Technique

A portable shiatsu massager that uses heat and deep-tissue kneading is placed on the upper thigh for toenail cases or lower arm for fingernail cases during injection of anesthetic to divert the patient’s attention from the surgical site (Figure). Kneading from the massage helps distract the patient from pain by introducing a competing, more pleasant, vibrating sensation that overrides pain signals; the relaxation component helps to diminish patient anxiety during injection.

Practice Implications

Use of a portable massager may reduce pain through both distraction and vibration. In a randomized clinical trial of 115 patients undergoing hand or facial surgery, patients who viewed a distraction video during the procedure reported a lower pain score compared to the control group (mean [SD] visual analog scale of pain score, 3.4 [2.6] vs 4.5 [2.6][P=.01]).⁴ In another randomized clinical trial of 25 patients undergoing lip augmentation, 92% of patients (23/25) in the vibration-assisted arm endorsed less pain during procedures compared to the arm without vibration (mean [SD] pain score, 3.82 [1.73] vs 5.6 [1.76][P<.001]).⁸

Utilization of a portable massager is a safe means of improving the patient experience; the distracting and relaxing effects and intense pulsations simultaneously reduce anxiety and pain during nail surgery. Controlled clinical trials are needed to evaluate its efficacy in diminishing both anxiety and pain during nail procedures compared to other analgesic methods.

FLOTCH (leukonychia totalis-trichilemmal cysts-ciliary dystrophy syndrome) syndrome is a rare genetic cutaneous disorder primarily characterized by multiple recurrent trichilemmal pilar cysts and leukonychia. It may be associated with ciliary dystrophy, koilonychia, and/or less frequently renal calculi and pancreatitis. This disorder often presents in an autosomal-dominant pattern of inheritance. Leukonychia and associated pilar cysts originally were termed Bauer syndrome in 1920 and later described in 1986 as FLOTCH syndrome secondary to the association with ciliary dystrophy. ^1,2 The term FLOTCH was coined by Friedel et al ¹ to describe a combination of diagnoses experienced by a family in which several members had multiple pilar cysts, leukonychia, and ciliary dystrophy. We present a 25-year-old Black woman with suspected FLOTCH syndrome who was seen in our clinic for enlarging cysts. 

Case Report

A 25-year-old Black woman with no notable medical history presented to the clinic for a surgical evaluation of cysts of several years’ duration that were enlarging and tender. Physical examination revealed multiple firm, fixed, tender nodules on the left superior parietal scalp, left inferior frontal scalp (Figure 1A), right inferior parietal scalp, right central postauricular skin, and right inferior occipital scalp. Similar-appearing cysts measuring 1.5 to 2 cm were seen on the left rib cage (Figure 1B) and left lateral forearm. Upon further examination, there was homogeneous, nonblanchable, white discoloration of all 10 fingernails consistent with true leukonychia (Figure 1C). When questioned about the nails, the patient stated they had been this color her whole life. Moreover, the patient confirmed that her brother’s nails had a similar appearance.

The patient subsequently underwent elliptical excision of the cysts located on the left medial forehead and left rib cage, and histopathology revealed trichilemmal pilar cysts with dystrophic calcification, dermal fibrosis, and mild chronic inflammation (Figure 2). The pathology report also noted that the anatomic site was somewhat unusual; however, the features were otherwise typical and diagnostic. Given the presentation of multiple pilar cysts throughout the body, leukonychia totalis, and positive family history, the patient was diagnosed with FLOTCH syndrome. Unfortunately, the patient was lost to follow-up following the excision, and no further management could be provided.

Comment

Leukonychia is an abnormality of the nail that results in a visible distribution of white color across the nail plate. It can be classified as totalis when covering the entire nail or partialis when covering localized areas of the nail. The disease also is categorized as acquired or inherited. Acquired leukonychia may appear after damage to a particular area of the nail or secondary to an underlying systemic disease, clinically appearing as white puncta or transverse striae. Hereditary leukonychia is rare, primarily covering the entire nail (totalis), and often is inherited in an autosomal-dominant pattern.^3,4 The appearance of this disease can be an isolated occurrence or may be a component of a condition such as FLOTCH syndrome, as proposed in this case.

Pilar cysts (also known as trichilemmal cysts) are benign, slowly growing, firm, subcutaneous nodules that are similar to epidermoid cysts but arise from the root sheaths of hair follicles. Pilar cysts are inherited in an autosomal-dominant pattern and are caused by a mutation involving a 2-hit mechanism of variants of the phospholipase C delta 1 gene, PLCD1. Patients typically present with multiple cysts,⁵ as in our case.

This association of leukonychia and multiple pilar cysts previously has been reported in 7 family lines.^1-3,6-9 The molecular basis of FLOTCH syndrome is unknown, and these combined diagnoses may be of syndromic nature. Histologic observations of leukonychia and the mechanism of the creation of pilar cysts suggest derivation from similar abnormal keratinization in the nail beds and hair follicles, respectively.⁶

The first familial association between leukonychia totalis and sebaceous cysts was described by Bauer² in 1920. In 1975, Bushkell and Gorlin⁷ reported a similar inherited association with the addition of a history of renal calculi. In 1986, Friedel et al¹ coined the term FLOTCH syndrome when reporting a case of an affected family presenting with leukonychia, recurrent cysts, and ciliary dystrophy. Slee et al⁸ reported 2 cases of pancreatitis experienced by patients presenting with these cysts and leukonychia. The etiology of the pancreatitis was unknown, leading researchers to believe it may be a complication associated with the spectrum of diseases.⁸ In 2008, Morin et al⁶ proposed that those with linked leukonychia and trichilemmal cysts may be at risk for neuromas or spinal tumors and suggested systematic screening after observing a family member with an ependymoma and bilateral multiple acoustic tumors. Rodríguez-Lojo et al³ described a 5-generation family with leukonychia totalis and numerous pilar cysts. Mutoh et al⁹ reported another 5-generation family with associated leukonychia and multiple pilar cysts as well as koilonychia. One family member had a reported history of renal calculus.⁹

In our case, FLOTCH syndrome was suspected given the patient’s concurrent pilar and follicular infundibular cysts. No specific treatment was indicated; however, as seen in prior cases and in ours, many patients prefer to have the cysts excised. A more comprehensive investigation could have revealed other associations, such as ciliary dystrophy, renal calculi, or pancreatitis. It is possible that in conjunction with the syndrome, patients could develop other such clinical manifestations. Pilar cysts most frequently are found on the scalp, yet in patients with concurrent leukonychia, the cysts have been shown to also develop in other regions of the body, as seen in our patient and in the case reported by Mutoh et al.⁹ Given the autosomal-dominant nature of this disease and the keratinizing structures affected, we confer with the hypotheses that a general keratin dysfunction is suspected. Further investigation is needed to determine the exact altered genetic mechanism or deficiency that may be causing this abnormal keratinization as well as a more extensive examination of patients to confirm if other described symptoms may be related.

FLOTCH (leukonychia totalis-trichilemmal cysts-ciliary dystrophy syndrome) syndrome is a rare genetic cutaneous disorder primarily characterized by multiple recurrent trichilemmal pilar cysts and leukonychia. It may be associated with ciliary dystrophy, koilonychia, and/or less frequently renal calculi and pancreatitis. This disorder often presents in an autosomal-dominant pattern of inheritance. Leukonychia and associated pilar cysts originally were termed Bauer syndrome in 1920 and later described in 1986 as FLOTCH syndrome secondary to the association with ciliary dystrophy. ^1,2 The term FLOTCH was coined by Friedel et al ¹ to describe a combination of diagnoses experienced by a family in which several members had multiple pilar cysts, leukonychia, and ciliary dystrophy. We present a 25-year-old Black woman with suspected FLOTCH syndrome who was seen in our clinic for enlarging cysts. 

Case Report

A 25-year-old Black woman with no notable medical history presented to the clinic for a surgical evaluation of cysts of several years’ duration that were enlarging and tender. Physical examination revealed multiple firm, fixed, tender nodules on the left superior parietal scalp, left inferior frontal scalp (Figure 1A), right inferior parietal scalp, right central postauricular skin, and right inferior occipital scalp. Similar-appearing cysts measuring 1.5 to 2 cm were seen on the left rib cage (Figure 1B) and left lateral forearm. Upon further examination, there was homogeneous, nonblanchable, white discoloration of all 10 fingernails consistent with true leukonychia (Figure 1C). When questioned about the nails, the patient stated they had been this color her whole life. Moreover, the patient confirmed that her brother’s nails had a similar appearance.

The patient subsequently underwent elliptical excision of the cysts located on the left medial forehead and left rib cage, and histopathology revealed trichilemmal pilar cysts with dystrophic calcification, dermal fibrosis, and mild chronic inflammation (Figure 2). The pathology report also noted that the anatomic site was somewhat unusual; however, the features were otherwise typical and diagnostic. Given the presentation of multiple pilar cysts throughout the body, leukonychia totalis, and positive family history, the patient was diagnosed with FLOTCH syndrome. Unfortunately, the patient was lost to follow-up following the excision, and no further management could be provided.

Comment

Leukonychia is an abnormality of the nail that results in a visible distribution of white color across the nail plate. It can be classified as totalis when covering the entire nail or partialis when covering localized areas of the nail. The disease also is categorized as acquired or inherited. Acquired leukonychia may appear after damage to a particular area of the nail or secondary to an underlying systemic disease, clinically appearing as white puncta or transverse striae. Hereditary leukonychia is rare, primarily covering the entire nail (totalis), and often is inherited in an autosomal-dominant pattern.^3,4 The appearance of this disease can be an isolated occurrence or may be a component of a condition such as FLOTCH syndrome, as proposed in this case.

Pilar cysts (also known as trichilemmal cysts) are benign, slowly growing, firm, subcutaneous nodules that are similar to epidermoid cysts but arise from the root sheaths of hair follicles. Pilar cysts are inherited in an autosomal-dominant pattern and are caused by a mutation involving a 2-hit mechanism of variants of the phospholipase C delta 1 gene, PLCD1. Patients typically present with multiple cysts,⁵ as in our case.

This association of leukonychia and multiple pilar cysts previously has been reported in 7 family lines.^1-3,6-9 The molecular basis of FLOTCH syndrome is unknown, and these combined diagnoses may be of syndromic nature. Histologic observations of leukonychia and the mechanism of the creation of pilar cysts suggest derivation from similar abnormal keratinization in the nail beds and hair follicles, respectively.⁶

The first familial association between leukonychia totalis and sebaceous cysts was described by Bauer² in 1920. In 1975, Bushkell and Gorlin⁷ reported a similar inherited association with the addition of a history of renal calculi. In 1986, Friedel et al¹ coined the term FLOTCH syndrome when reporting a case of an affected family presenting with leukonychia, recurrent cysts, and ciliary dystrophy. Slee et al⁸ reported 2 cases of pancreatitis experienced by patients presenting with these cysts and leukonychia. The etiology of the pancreatitis was unknown, leading researchers to believe it may be a complication associated with the spectrum of diseases.⁸ In 2008, Morin et al⁶ proposed that those with linked leukonychia and trichilemmal cysts may be at risk for neuromas or spinal tumors and suggested systematic screening after observing a family member with an ependymoma and bilateral multiple acoustic tumors. Rodríguez-Lojo et al³ described a 5-generation family with leukonychia totalis and numerous pilar cysts. Mutoh et al⁹ reported another 5-generation family with associated leukonychia and multiple pilar cysts as well as koilonychia. One family member had a reported history of renal calculus.⁹

In our case, FLOTCH syndrome was suspected given the patient’s concurrent pilar and follicular infundibular cysts. No specific treatment was indicated; however, as seen in prior cases and in ours, many patients prefer to have the cysts excised. A more comprehensive investigation could have revealed other associations, such as ciliary dystrophy, renal calculi, or pancreatitis. It is possible that in conjunction with the syndrome, patients could develop other such clinical manifestations. Pilar cysts most frequently are found on the scalp, yet in patients with concurrent leukonychia, the cysts have been shown to also develop in other regions of the body, as seen in our patient and in the case reported by Mutoh et al.⁹ Given the autosomal-dominant nature of this disease and the keratinizing structures affected, we confer with the hypotheses that a general keratin dysfunction is suspected. Further investigation is needed to determine the exact altered genetic mechanism or deficiency that may be causing this abnormal keratinization as well as a more extensive examination of patients to confirm if other described symptoms may be related.

FLOTCH (leukonychia totalis-trichilemmal cysts-ciliary dystrophy syndrome) syndrome is a rare genetic cutaneous disorder primarily characterized by multiple recurrent trichilemmal pilar cysts and leukonychia. It may be associated with ciliary dystrophy, koilonychia, and/or less frequently renal calculi and pancreatitis. This disorder often presents in an autosomal-dominant pattern of inheritance. Leukonychia and associated pilar cysts originally were termed Bauer syndrome in 1920 and later described in 1986 as FLOTCH syndrome secondary to the association with ciliary dystrophy. ^1,2 The term FLOTCH was coined by Friedel et al ¹ to describe a combination of diagnoses experienced by a family in which several members had multiple pilar cysts, leukonychia, and ciliary dystrophy. We present a 25-year-old Black woman with suspected FLOTCH syndrome who was seen in our clinic for enlarging cysts. 

Case Report

A 25-year-old Black woman with no notable medical history presented to the clinic for a surgical evaluation of cysts of several years’ duration that were enlarging and tender. Physical examination revealed multiple firm, fixed, tender nodules on the left superior parietal scalp, left inferior frontal scalp (Figure 1A), right inferior parietal scalp, right central postauricular skin, and right inferior occipital scalp. Similar-appearing cysts measuring 1.5 to 2 cm were seen on the left rib cage (Figure 1B) and left lateral forearm. Upon further examination, there was homogeneous, nonblanchable, white discoloration of all 10 fingernails consistent with true leukonychia (Figure 1C). When questioned about the nails, the patient stated they had been this color her whole life. Moreover, the patient confirmed that her brother’s nails had a similar appearance.

The patient subsequently underwent elliptical excision of the cysts located on the left medial forehead and left rib cage, and histopathology revealed trichilemmal pilar cysts with dystrophic calcification, dermal fibrosis, and mild chronic inflammation (Figure 2). The pathology report also noted that the anatomic site was somewhat unusual; however, the features were otherwise typical and diagnostic. Given the presentation of multiple pilar cysts throughout the body, leukonychia totalis, and positive family history, the patient was diagnosed with FLOTCH syndrome. Unfortunately, the patient was lost to follow-up following the excision, and no further management could be provided.

Comment

Leukonychia is an abnormality of the nail that results in a visible distribution of white color across the nail plate. It can be classified as totalis when covering the entire nail or partialis when covering localized areas of the nail. The disease also is categorized as acquired or inherited. Acquired leukonychia may appear after damage to a particular area of the nail or secondary to an underlying systemic disease, clinically appearing as white puncta or transverse striae. Hereditary leukonychia is rare, primarily covering the entire nail (totalis), and often is inherited in an autosomal-dominant pattern.^3,4 The appearance of this disease can be an isolated occurrence or may be a component of a condition such as FLOTCH syndrome, as proposed in this case.

Pilar cysts (also known as trichilemmal cysts) are benign, slowly growing, firm, subcutaneous nodules that are similar to epidermoid cysts but arise from the root sheaths of hair follicles. Pilar cysts are inherited in an autosomal-dominant pattern and are caused by a mutation involving a 2-hit mechanism of variants of the phospholipase C delta 1 gene, PLCD1. Patients typically present with multiple cysts,⁵ as in our case.

This association of leukonychia and multiple pilar cysts previously has been reported in 7 family lines.^1-3,6-9 The molecular basis of FLOTCH syndrome is unknown, and these combined diagnoses may be of syndromic nature. Histologic observations of leukonychia and the mechanism of the creation of pilar cysts suggest derivation from similar abnormal keratinization in the nail beds and hair follicles, respectively.⁶

The first familial association between leukonychia totalis and sebaceous cysts was described by Bauer² in 1920. In 1975, Bushkell and Gorlin⁷ reported a similar inherited association with the addition of a history of renal calculi. In 1986, Friedel et al¹ coined the term FLOTCH syndrome when reporting a case of an affected family presenting with leukonychia, recurrent cysts, and ciliary dystrophy. Slee et al⁸ reported 2 cases of pancreatitis experienced by patients presenting with these cysts and leukonychia. The etiology of the pancreatitis was unknown, leading researchers to believe it may be a complication associated with the spectrum of diseases.⁸ In 2008, Morin et al⁶ proposed that those with linked leukonychia and trichilemmal cysts may be at risk for neuromas or spinal tumors and suggested systematic screening after observing a family member with an ependymoma and bilateral multiple acoustic tumors. Rodríguez-Lojo et al³ described a 5-generation family with leukonychia totalis and numerous pilar cysts. Mutoh et al⁹ reported another 5-generation family with associated leukonychia and multiple pilar cysts as well as koilonychia. One family member had a reported history of renal calculus.⁹

In our case, FLOTCH syndrome was suspected given the patient’s concurrent pilar and follicular infundibular cysts. No specific treatment was indicated; however, as seen in prior cases and in ours, many patients prefer to have the cysts excised. A more comprehensive investigation could have revealed other associations, such as ciliary dystrophy, renal calculi, or pancreatitis. It is possible that in conjunction with the syndrome, patients could develop other such clinical manifestations. Pilar cysts most frequently are found on the scalp, yet in patients with concurrent leukonychia, the cysts have been shown to also develop in other regions of the body, as seen in our patient and in the case reported by Mutoh et al.⁹ Given the autosomal-dominant nature of this disease and the keratinizing structures affected, we confer with the hypotheses that a general keratin dysfunction is suspected. Further investigation is needed to determine the exact altered genetic mechanism or deficiency that may be causing this abnormal keratinization as well as a more extensive examination of patients to confirm if other described symptoms may be related.

Dermatology residency positions continue to be highly coveted among applicants in the match. In 2019, dermatology proved to be the most competitive specialty, with 36.3% of US medical school seniors and independent applicants going unmatched.¹ Prior to the transition to a pass/fail system, the mean US Medical Licensing Examination (USMLE) Step 1 score for matched applicants increased from 247 in 2014 to 251 in 2019. The growing number of scholarly activities reported by applicants has contributed to the competitiveness of the specialty. In 2018, the mean number of abstracts, presentations, and publications reported by matched applicants was 14.71, which was higher than other competitive specialties, including orthopedic surgery and otolaryngology (11.5 and 10.4, respectively). Dermatology applicants who did not match in 2018 reported a mean of 8.6 abstracts, presentations, and publications, which was on par with successful applicants in many other specialties.¹ In 2011, Stratman and Ness² found that publishing manuscripts and listing research experience were factors strongly associated with matching into dermatology for reapplicants. These trends in reported research have added pressure for applicants to increase their publications.

Given that many students do not choose a career in dermatology until later in medical school, some students choose to take a gap year between their third and fourth years of medical school to pursue a research fellowship (RF) and produce publications, in theory to increase the chances of matching in dermatology. A survey of dermatology applicants conducted by Costello et al³ in 2021 found that, of the students who completed a gap year (n=90; 31.25%), 78.7% (n=71) of them completed an RF, and those who completed RFs were more likely to match at top dermatology residency programs (P<.01). The authors also reported that there was no significant difference in overall match rates between gap-year and non–gap-year applicants.³ Another survey of 328 medical students found that the most common reason students take years off for research during medical school is to increase competitiveness for residency application.⁴ Although it is clear that students completing an RF often find success in the match, there are limited published data on how those involved in selecting dermatology residents view this additional year. We surveyed faculty members participating in the resident selection process to assess their viewpoints on how RFs factored into an applicant’s odds of matching into dermatology residency and performance as a resident.

Materials and Methods

An institutional review board application was submitted through the Geisinger Health System (Danville, Pennsylvania), and an exemption to complete the survey was granted. The survey consisted of 16 questions via REDCap electronic data capture and was sent to a listserve of dermatology program directors who were asked to distribute the survey to program chairs and faculty members within their department. Survey questions evaluated the participants’ involvement in medical student advising and the residency selection process. Questions relating to the respondents’ opinions were based on a 5-point Likert scale on level of agreement (1=strongly agree; 5=strongly disagree) or importance (1=a great deal; 5=not at all). All responses were collected anonymously. Data points were compiled and analyzed using REDCap. Statistical analysis via χ² tests were conducted when appropriate.

Results

The survey was sent to 142 individuals and distributed to faculty members within those departments between August 16, 2019, and September 24, 2019. The survey elicited a total of 110 respondents. Demographic information is shown in eTable 1. Of these respondents, 35.5% were program directors, 23.6% were program chairs, 3.6% were both program director and program chair, and 37.3% were core faculty members. Although respondents’ roles were varied, 96.4% indicated that they were involved in both advising medical students and in selecting residents.

None of the respondents indicated that they always recommend that students complete an RF, and only 4.5% indicated that they usually recommend it; 40% of respondents rarely or never recommend an RF, while 55.5% sometimes recommend it. Although there was a variety of responses to how frequently faculty members recommend an RF, almost all respondents (98.2%) agreed that the reason medical students pursued an RF prior to residency application was to increase the competitiveness of their residency application. However, 20% of respondents believed that students in this cohort were seeking to gain a deeper understanding of the specialty, and 27.3% thought that this cohort had genuine interest in research. Interestingly, despite the medical students’ intentions of choosing an RF, most respondents (67.3%) agreed or strongly agreed that the publications produced by fellows make an impact on the dermatologic scientific community.

Although some respondents indicated that completion of an RF positively impacts resident performance with regard to patient care, most indicated that the impact was a little (26.4%) or not at all (50%). Additionally, a minority of respondents (11.8%) believed that RFs positively impact resident performance on in-service and board examinations at least a moderate amount, with 62.7% indicating no positive impact at all. Only 12.7% of participants agreed or strongly agreed that completion of an RF led to increased applicant involvement in research throughout their career, and most (73.6%) believed there were downsides to completing an RF. Finally, only 20% agreed or strongly agreed that students who completed an RF were more dedicated to the field of dermatology (eTable 2).

Further evaluation of the data indicated that the perceived utility of RFs did not affect respondents’ recommendation on whether to pursue an RF or not. For example, of the 4.5% of respondents who indicated that they always or usually recommended RFs, only 1 respondent believed that students who completed an RF were more dedicated to the field of dermatology than those who did not. Although 55.5% of respondents answered that they sometimes recommended completion of an RF, less than a quarter of this group believed that students who completed an RF were more likely to be heavily involved in research throughout their career (P=.99).

Overall, 11.8% of respondents indicated that completion of a dermatology RF influenced the evaluation of an applicant a great deal or a lot, while 53.6% of respondents indicated a little or no influence at all. Most respondents (62.8%) agreed or strongly agreed that completion of an RF can compensate for flaws in a residency application. Furthermore, when asked if completion of an RF could set 2 otherwise equivocal applicants apart from one another, 46.4% of respondents agreed or strongly agreed with the statement, while only 17.3% disagreed or strongly disagreed (eTable 2).

Comment

This study characterized how completion of an RF is viewed by those involved in advising medical students and selecting dermatology residents. The growing pressure for applicants to increase the number of publications combined with the competitiveness of applying for a dermatology residency position has led to increased participation in RFs. However, studies have found that students who completed an RF often did so despite a lack of interest.⁴ Nonetheless, little is known about how this is perceived by those involved in choosing residents.

We found that few respondents always or usually advised applicants to complete an RF, but the majority sometimes recommended them, demonstrating the complexity of this issue. Completion of an RF impacted 11.8% of respondents’ overall opinion of an applicant a lot or a great deal, while most respondents (53.6%) were influenced a little or not at all. However, 46.4% of respondents indicated that completion of a dermatology RF would set apart 2 applicants of otherwise equal standing, and 62.8% agreed or strongly agreed that completion of an RF would compensate for flaws in an application. These responses align with the findings of a study conducted by Kaffenberger et al,⁵ who surveyed members of the Association of Professors of Dermatology and found that 74.5% (73/98) of mentors almost always or sometimes recommended a research gap year for reasons that included low grades, low USMLE Step scores, and little research. These data suggest that completion of an RF can give a competitive advantage to applicants despite most advisors acknowledging that these applicants are not likely to be involved in research throughout their careers, perform better on standardized examinations, or provide better patient care.

Given the complexity of this issue, respondents may not have been able to accurately answer the question about how much an RF influenced their overall opinion of an applicant because of subconscious bias. Furthermore, respondents likely tailored their recommendations to complete an RF based on individual applicant strengths and weaknesses, and the specific reasons why one may recommend an RF need to be further investigated.

Although there may be other perceived advantages to RFs that were not captured by our survey, completion of a dermatology RF is not without disadvantages. Fellowships often are unfunded and offered in cities with high costs of living. Additionally, students are forced to delay graduation from medical school by a year at minimum and continue to accrue interest on medical school loans during this time. The financial burdens of completing an RF may exclude students of lower socioeconomic status and contribute to a decrease in diversity within the field. Dermatology has been found to be the second least diverse specialty, behind orthopedics.⁶ Soliman et al⁷ found that racial minorities and low-income students were more likely to cite socioeconomic barriers as factors involved in their decision not to pursue a career in dermatology. This notion was supported by Rinderknecht et al,⁸ who found that Black and Latinx dermatology applicants were more likely to come from disadvantaged backgrounds, and Black applicants were more likely to indicate financial concerns as their primary reason for not pursuing an RF. The impact of accumulated student debt and decreased access should be carefully weighed against the potential benefits of an RF. However, as the USMLE transitions their Step 1 score reporting from numerical to a pass/fail system, it also is possible that dermatology programs will place more emphasis on research productivity when evaluating applications for residency. Overall, the decision to recommend an RF represents an extremely complex topic, as indicated by the results of this study.

Limitations—Our survey-based study is limited by response rate and response bias. Despite the large number of responses, the overall response rate cannot be determined because it is unknown how many total faculty members actually received the survey. Moreover, data collected from current dermatology residents who have completed RFs vs those who have not as they pertain to resident performance and preparedness for the rigors of a dermatology residency would be useful.

Dermatology residency positions continue to be highly coveted among applicants in the match. In 2019, dermatology proved to be the most competitive specialty, with 36.3% of US medical school seniors and independent applicants going unmatched.¹ Prior to the transition to a pass/fail system, the mean US Medical Licensing Examination (USMLE) Step 1 score for matched applicants increased from 247 in 2014 to 251 in 2019. The growing number of scholarly activities reported by applicants has contributed to the competitiveness of the specialty. In 2018, the mean number of abstracts, presentations, and publications reported by matched applicants was 14.71, which was higher than other competitive specialties, including orthopedic surgery and otolaryngology (11.5 and 10.4, respectively). Dermatology applicants who did not match in 2018 reported a mean of 8.6 abstracts, presentations, and publications, which was on par with successful applicants in many other specialties.¹ In 2011, Stratman and Ness² found that publishing manuscripts and listing research experience were factors strongly associated with matching into dermatology for reapplicants. These trends in reported research have added pressure for applicants to increase their publications.

Given that many students do not choose a career in dermatology until later in medical school, some students choose to take a gap year between their third and fourth years of medical school to pursue a research fellowship (RF) and produce publications, in theory to increase the chances of matching in dermatology. A survey of dermatology applicants conducted by Costello et al³ in 2021 found that, of the students who completed a gap year (n=90; 31.25%), 78.7% (n=71) of them completed an RF, and those who completed RFs were more likely to match at top dermatology residency programs (P<.01). The authors also reported that there was no significant difference in overall match rates between gap-year and non–gap-year applicants.³ Another survey of 328 medical students found that the most common reason students take years off for research during medical school is to increase competitiveness for residency application.⁴ Although it is clear that students completing an RF often find success in the match, there are limited published data on how those involved in selecting dermatology residents view this additional year. We surveyed faculty members participating in the resident selection process to assess their viewpoints on how RFs factored into an applicant’s odds of matching into dermatology residency and performance as a resident.

Materials and Methods

An institutional review board application was submitted through the Geisinger Health System (Danville, Pennsylvania), and an exemption to complete the survey was granted. The survey consisted of 16 questions via REDCap electronic data capture and was sent to a listserve of dermatology program directors who were asked to distribute the survey to program chairs and faculty members within their department. Survey questions evaluated the participants’ involvement in medical student advising and the residency selection process. Questions relating to the respondents’ opinions were based on a 5-point Likert scale on level of agreement (1=strongly agree; 5=strongly disagree) or importance (1=a great deal; 5=not at all). All responses were collected anonymously. Data points were compiled and analyzed using REDCap. Statistical analysis via χ² tests were conducted when appropriate.

Results

The survey was sent to 142 individuals and distributed to faculty members within those departments between August 16, 2019, and September 24, 2019. The survey elicited a total of 110 respondents. Demographic information is shown in eTable 1. Of these respondents, 35.5% were program directors, 23.6% were program chairs, 3.6% were both program director and program chair, and 37.3% were core faculty members. Although respondents’ roles were varied, 96.4% indicated that they were involved in both advising medical students and in selecting residents.

None of the respondents indicated that they always recommend that students complete an RF, and only 4.5% indicated that they usually recommend it; 40% of respondents rarely or never recommend an RF, while 55.5% sometimes recommend it. Although there was a variety of responses to how frequently faculty members recommend an RF, almost all respondents (98.2%) agreed that the reason medical students pursued an RF prior to residency application was to increase the competitiveness of their residency application. However, 20% of respondents believed that students in this cohort were seeking to gain a deeper understanding of the specialty, and 27.3% thought that this cohort had genuine interest in research. Interestingly, despite the medical students’ intentions of choosing an RF, most respondents (67.3%) agreed or strongly agreed that the publications produced by fellows make an impact on the dermatologic scientific community.

Although some respondents indicated that completion of an RF positively impacts resident performance with regard to patient care, most indicated that the impact was a little (26.4%) or not at all (50%). Additionally, a minority of respondents (11.8%) believed that RFs positively impact resident performance on in-service and board examinations at least a moderate amount, with 62.7% indicating no positive impact at all. Only 12.7% of participants agreed or strongly agreed that completion of an RF led to increased applicant involvement in research throughout their career, and most (73.6%) believed there were downsides to completing an RF. Finally, only 20% agreed or strongly agreed that students who completed an RF were more dedicated to the field of dermatology (eTable 2).

Further evaluation of the data indicated that the perceived utility of RFs did not affect respondents’ recommendation on whether to pursue an RF or not. For example, of the 4.5% of respondents who indicated that they always or usually recommended RFs, only 1 respondent believed that students who completed an RF were more dedicated to the field of dermatology than those who did not. Although 55.5% of respondents answered that they sometimes recommended completion of an RF, less than a quarter of this group believed that students who completed an RF were more likely to be heavily involved in research throughout their career (P=.99).

Overall, 11.8% of respondents indicated that completion of a dermatology RF influenced the evaluation of an applicant a great deal or a lot, while 53.6% of respondents indicated a little or no influence at all. Most respondents (62.8%) agreed or strongly agreed that completion of an RF can compensate for flaws in a residency application. Furthermore, when asked if completion of an RF could set 2 otherwise equivocal applicants apart from one another, 46.4% of respondents agreed or strongly agreed with the statement, while only 17.3% disagreed or strongly disagreed (eTable 2).

Comment

This study characterized how completion of an RF is viewed by those involved in advising medical students and selecting dermatology residents. The growing pressure for applicants to increase the number of publications combined with the competitiveness of applying for a dermatology residency position has led to increased participation in RFs. However, studies have found that students who completed an RF often did so despite a lack of interest.⁴ Nonetheless, little is known about how this is perceived by those involved in choosing residents.

We found that few respondents always or usually advised applicants to complete an RF, but the majority sometimes recommended them, demonstrating the complexity of this issue. Completion of an RF impacted 11.8% of respondents’ overall opinion of an applicant a lot or a great deal, while most respondents (53.6%) were influenced a little or not at all. However, 46.4% of respondents indicated that completion of a dermatology RF would set apart 2 applicants of otherwise equal standing, and 62.8% agreed or strongly agreed that completion of an RF would compensate for flaws in an application. These responses align with the findings of a study conducted by Kaffenberger et al,⁵ who surveyed members of the Association of Professors of Dermatology and found that 74.5% (73/98) of mentors almost always or sometimes recommended a research gap year for reasons that included low grades, low USMLE Step scores, and little research. These data suggest that completion of an RF can give a competitive advantage to applicants despite most advisors acknowledging that these applicants are not likely to be involved in research throughout their careers, perform better on standardized examinations, or provide better patient care.

Given the complexity of this issue, respondents may not have been able to accurately answer the question about how much an RF influenced their overall opinion of an applicant because of subconscious bias. Furthermore, respondents likely tailored their recommendations to complete an RF based on individual applicant strengths and weaknesses, and the specific reasons why one may recommend an RF need to be further investigated.

Although there may be other perceived advantages to RFs that were not captured by our survey, completion of a dermatology RF is not without disadvantages. Fellowships often are unfunded and offered in cities with high costs of living. Additionally, students are forced to delay graduation from medical school by a year at minimum and continue to accrue interest on medical school loans during this time. The financial burdens of completing an RF may exclude students of lower socioeconomic status and contribute to a decrease in diversity within the field. Dermatology has been found to be the second least diverse specialty, behind orthopedics.⁶ Soliman et al⁷ found that racial minorities and low-income students were more likely to cite socioeconomic barriers as factors involved in their decision not to pursue a career in dermatology. This notion was supported by Rinderknecht et al,⁸ who found that Black and Latinx dermatology applicants were more likely to come from disadvantaged backgrounds, and Black applicants were more likely to indicate financial concerns as their primary reason for not pursuing an RF. The impact of accumulated student debt and decreased access should be carefully weighed against the potential benefits of an RF. However, as the USMLE transitions their Step 1 score reporting from numerical to a pass/fail system, it also is possible that dermatology programs will place more emphasis on research productivity when evaluating applications for residency. Overall, the decision to recommend an RF represents an extremely complex topic, as indicated by the results of this study.

Limitations—Our survey-based study is limited by response rate and response bias. Despite the large number of responses, the overall response rate cannot be determined because it is unknown how many total faculty members actually received the survey. Moreover, data collected from current dermatology residents who have completed RFs vs those who have not as they pertain to resident performance and preparedness for the rigors of a dermatology residency would be useful.

Dermatology residency positions continue to be highly coveted among applicants in the match. In 2019, dermatology proved to be the most competitive specialty, with 36.3% of US medical school seniors and independent applicants going unmatched.¹ Prior to the transition to a pass/fail system, the mean US Medical Licensing Examination (USMLE) Step 1 score for matched applicants increased from 247 in 2014 to 251 in 2019. The growing number of scholarly activities reported by applicants has contributed to the competitiveness of the specialty. In 2018, the mean number of abstracts, presentations, and publications reported by matched applicants was 14.71, which was higher than other competitive specialties, including orthopedic surgery and otolaryngology (11.5 and 10.4, respectively). Dermatology applicants who did not match in 2018 reported a mean of 8.6 abstracts, presentations, and publications, which was on par with successful applicants in many other specialties.¹ In 2011, Stratman and Ness² found that publishing manuscripts and listing research experience were factors strongly associated with matching into dermatology for reapplicants. These trends in reported research have added pressure for applicants to increase their publications.

Given that many students do not choose a career in dermatology until later in medical school, some students choose to take a gap year between their third and fourth years of medical school to pursue a research fellowship (RF) and produce publications, in theory to increase the chances of matching in dermatology. A survey of dermatology applicants conducted by Costello et al³ in 2021 found that, of the students who completed a gap year (n=90; 31.25%), 78.7% (n=71) of them completed an RF, and those who completed RFs were more likely to match at top dermatology residency programs (P<.01). The authors also reported that there was no significant difference in overall match rates between gap-year and non–gap-year applicants.³ Another survey of 328 medical students found that the most common reason students take years off for research during medical school is to increase competitiveness for residency application.⁴ Although it is clear that students completing an RF often find success in the match, there are limited published data on how those involved in selecting dermatology residents view this additional year. We surveyed faculty members participating in the resident selection process to assess their viewpoints on how RFs factored into an applicant’s odds of matching into dermatology residency and performance as a resident.

Materials and Methods

An institutional review board application was submitted through the Geisinger Health System (Danville, Pennsylvania), and an exemption to complete the survey was granted. The survey consisted of 16 questions via REDCap electronic data capture and was sent to a listserve of dermatology program directors who were asked to distribute the survey to program chairs and faculty members within their department. Survey questions evaluated the participants’ involvement in medical student advising and the residency selection process. Questions relating to the respondents’ opinions were based on a 5-point Likert scale on level of agreement (1=strongly agree; 5=strongly disagree) or importance (1=a great deal; 5=not at all). All responses were collected anonymously. Data points were compiled and analyzed using REDCap. Statistical analysis via χ² tests were conducted when appropriate.

Results

The survey was sent to 142 individuals and distributed to faculty members within those departments between August 16, 2019, and September 24, 2019. The survey elicited a total of 110 respondents. Demographic information is shown in eTable 1. Of these respondents, 35.5% were program directors, 23.6% were program chairs, 3.6% were both program director and program chair, and 37.3% were core faculty members. Although respondents’ roles were varied, 96.4% indicated that they were involved in both advising medical students and in selecting residents.

None of the respondents indicated that they always recommend that students complete an RF, and only 4.5% indicated that they usually recommend it; 40% of respondents rarely or never recommend an RF, while 55.5% sometimes recommend it. Although there was a variety of responses to how frequently faculty members recommend an RF, almost all respondents (98.2%) agreed that the reason medical students pursued an RF prior to residency application was to increase the competitiveness of their residency application. However, 20% of respondents believed that students in this cohort were seeking to gain a deeper understanding of the specialty, and 27.3% thought that this cohort had genuine interest in research. Interestingly, despite the medical students’ intentions of choosing an RF, most respondents (67.3%) agreed or strongly agreed that the publications produced by fellows make an impact on the dermatologic scientific community.

Although some respondents indicated that completion of an RF positively impacts resident performance with regard to patient care, most indicated that the impact was a little (26.4%) or not at all (50%). Additionally, a minority of respondents (11.8%) believed that RFs positively impact resident performance on in-service and board examinations at least a moderate amount, with 62.7% indicating no positive impact at all. Only 12.7% of participants agreed or strongly agreed that completion of an RF led to increased applicant involvement in research throughout their career, and most (73.6%) believed there were downsides to completing an RF. Finally, only 20% agreed or strongly agreed that students who completed an RF were more dedicated to the field of dermatology (eTable 2).

Further evaluation of the data indicated that the perceived utility of RFs did not affect respondents’ recommendation on whether to pursue an RF or not. For example, of the 4.5% of respondents who indicated that they always or usually recommended RFs, only 1 respondent believed that students who completed an RF were more dedicated to the field of dermatology than those who did not. Although 55.5% of respondents answered that they sometimes recommended completion of an RF, less than a quarter of this group believed that students who completed an RF were more likely to be heavily involved in research throughout their career (P=.99).

Overall, 11.8% of respondents indicated that completion of a dermatology RF influenced the evaluation of an applicant a great deal or a lot, while 53.6% of respondents indicated a little or no influence at all. Most respondents (62.8%) agreed or strongly agreed that completion of an RF can compensate for flaws in a residency application. Furthermore, when asked if completion of an RF could set 2 otherwise equivocal applicants apart from one another, 46.4% of respondents agreed or strongly agreed with the statement, while only 17.3% disagreed or strongly disagreed (eTable 2).

Comment

This study characterized how completion of an RF is viewed by those involved in advising medical students and selecting dermatology residents. The growing pressure for applicants to increase the number of publications combined with the competitiveness of applying for a dermatology residency position has led to increased participation in RFs. However, studies have found that students who completed an RF often did so despite a lack of interest.⁴ Nonetheless, little is known about how this is perceived by those involved in choosing residents.

We found that few respondents always or usually advised applicants to complete an RF, but the majority sometimes recommended them, demonstrating the complexity of this issue. Completion of an RF impacted 11.8% of respondents’ overall opinion of an applicant a lot or a great deal, while most respondents (53.6%) were influenced a little or not at all. However, 46.4% of respondents indicated that completion of a dermatology RF would set apart 2 applicants of otherwise equal standing, and 62.8% agreed or strongly agreed that completion of an RF would compensate for flaws in an application. These responses align with the findings of a study conducted by Kaffenberger et al,⁵ who surveyed members of the Association of Professors of Dermatology and found that 74.5% (73/98) of mentors almost always or sometimes recommended a research gap year for reasons that included low grades, low USMLE Step scores, and little research. These data suggest that completion of an RF can give a competitive advantage to applicants despite most advisors acknowledging that these applicants are not likely to be involved in research throughout their careers, perform better on standardized examinations, or provide better patient care.

Given the complexity of this issue, respondents may not have been able to accurately answer the question about how much an RF influenced their overall opinion of an applicant because of subconscious bias. Furthermore, respondents likely tailored their recommendations to complete an RF based on individual applicant strengths and weaknesses, and the specific reasons why one may recommend an RF need to be further investigated.

Although there may be other perceived advantages to RFs that were not captured by our survey, completion of a dermatology RF is not without disadvantages. Fellowships often are unfunded and offered in cities with high costs of living. Additionally, students are forced to delay graduation from medical school by a year at minimum and continue to accrue interest on medical school loans during this time. The financial burdens of completing an RF may exclude students of lower socioeconomic status and contribute to a decrease in diversity within the field. Dermatology has been found to be the second least diverse specialty, behind orthopedics.⁶ Soliman et al⁷ found that racial minorities and low-income students were more likely to cite socioeconomic barriers as factors involved in their decision not to pursue a career in dermatology. This notion was supported by Rinderknecht et al,⁸ who found that Black and Latinx dermatology applicants were more likely to come from disadvantaged backgrounds, and Black applicants were more likely to indicate financial concerns as their primary reason for not pursuing an RF. The impact of accumulated student debt and decreased access should be carefully weighed against the potential benefits of an RF. However, as the USMLE transitions their Step 1 score reporting from numerical to a pass/fail system, it also is possible that dermatology programs will place more emphasis on research productivity when evaluating applications for residency. Overall, the decision to recommend an RF represents an extremely complex topic, as indicated by the results of this study.

Limitations—Our survey-based study is limited by response rate and response bias. Despite the large number of responses, the overall response rate cannot be determined because it is unknown how many total faculty members actually received the survey. Moreover, data collected from current dermatology residents who have completed RFs vs those who have not as they pertain to resident performance and preparedness for the rigors of a dermatology residency would be useful.

Melasma is a complex, long-lasting, acquired dermatologic pigmentation disorder resulting in grey-brown patches that last for more than 3 months. Sun-exposed areas including the nose, cheeks, forehead, and forearms are most likely to be affected.¹ In Southeast Asia, 0.25% to 4% of the population affected by melasma is aged 30 to 40 years.² In particular, melasma is a concern among pregnant women due to increased levels of melanocyte-stimulating hormones (MSHs) and is impacted by genetics, hormonal influence, and exposure to UV light.^3,4 In Pakistan, approximately 46% of women are affected by melasma during pregnancy.^2,5 Although few studies have focused on the clinical approaches to melasma in darker skin types, it continues to disproportionately affect the skin of color population.⁴

The areas of hyperpigmentation seen in melasma exhibit increased deposition of melanin in the epidermis and dermis, but melanocytes are not elevated. However, in areas of hyperpigmentation, the melanocytes are larger and more dendritic and demonstrate an increased level of melanogenesis.⁶ During pregnancy, especially in the third trimester, elevated levels of estrogen, progesterone, and MSH often are found in association with melasma.⁷ Tyrosinase (TYR) activity increases and cellular proliferation is reduced after treatment of melanocytes in culture with β-estradiol.⁸ Sex steroids increase transcription of genes encoding melanogenic enzymes in normal human melanocytes, especially TYR.⁹ These results are consistent with the notable increases in melanin synthesis and TYR activity reported for normal human melanocytes under similar conditions in culture.¹⁰ Because melanocytes contain both cytosolic and nuclear estrogen receptors, melanocytes in patients with melasma may be inherently more sensitive to the stimulatory effects of estrogens and possibly other steroid hormones.¹¹

The current treatment options for melasma have varying levels of success and include topical depigmenting agents such as hydroquinone, tretinoin, azelaic acid, kojic acid, and corticosteroids; dermabrasion; and chemical peels.^12-14 Chemical peels with glycolic acid, salicylic acid, lactic acid, trichloroacetic acid, and phenol, as well as laser therapy, are reliable management options.^13,14 Traditionally, melasma has been treated with a combination of modalities along with photoprotection and trigger avoidance.¹²

The efficacy and safety of the available therapies for melasma are still controversial and require further exploration. In recent years, off-label tranexamic acid (TA) has emerged as a potential therapy for melasma. Although the mechanism of action remains unclear, TA may inhibit melanin synthesis by blocking the interaction between melanocytes and keratinocytes.¹⁵ Tranexamic acid also may reverse the abnormal dermal changes associated with melasma by inhibiting melanogenesis and angiogenesis.¹⁶

Although various therapeutic options exist for melasma, the search for a reliable option in patients with darker skin types continues.¹³ We sought to evaluate the efficacy of TA solution 5% in reducing the severity of melasma in South Asian patients, thereby improving patient outcomes and maximizing patient satisfaction. Topical TA is inexpensive and readily accessible and does not cause systemic side effects. These qualities make it a promising treatment compared to traditional therapies.

Methods

We conducted a randomized controlled trial at Rawalpindi Medical Institute (Punjab, Pakistan). The researchers obtained informed consent for all enrolled patients. Cases were sampled from the original patient population seen at the office using nonprobability consecutive sampling. The sample size was calculated with a 95% CI, margin of error of 9%, and expected percentage of efficacy of 86.1% by using TA solution 5%. South Asian male and female patients aged 20 to 45 years with melasma were included in the analysis. Patients were excluded if they were already taking TA, oral contraceptive pills, or photosensitizing drugs (eg, nonsteroidal anti-inflammatory drugs, tetracyclines, phenytoin, carbamazepine); were pregnant; had chronic kidney disease (creatinine >2.0 mg/dL); had cardiac abnormalities (abnormal electrocardiogram); had hematologic disorders (international normalized ratio >2); or had received another melasma treatment within the last 3 to 6 months.

All enrolled patients underwent a detailed history and physical examination. Patient demographics were subsequently noted, including age, sex, history of diabetes mellitus or hypertension, and duration of melasma. The melasma area and severity index (MASI) score of each patient was calculated at baseline, and a corresponding photograph was taken.

The topical solution was prepared with 5 g of TA dissolved in 10 cc of ethanol at 96 °F, 10 cc of 1,3-butanediol, and distilled water up to 100 cc. The TA solution was applied to the affected areas once daily by the patient for 12 weeks. Each application covered the affected areas completely. Patients were instructed to apply sunscreen with sun protection factor 60 to those same areas for UV protection after 15 minutes of TA application. Biweekly follow-ups were scheduled during the trial, and the MASI score was recorded at these visits. If the mean MASI score was reduced by half after 12 weeks of treatment, then the treatment was considered efficacious with a 95% CI.

The percentage reduction from baseline was calculated as follows: percentage reduction=(baseline score– follow-up score)/baseline score×100.

Statistical Analysis—Data were analyzed in SPSS Statistics 25 (IBM). The quantitative variables of age, duration of melasma, and body mass index were presented as mean (SD). Qualitative variables such as sex, history of diabetes mellitus or hypertension, site of melasma, and efficacy were presented as frequencies and percentages. Mean MASI scores at baseline and 12 weeks posttreatment were compared using a paired t test (P≤.05). Data were stratified for age, sex, history of diabetes mellitus or hypertension, site of melasma, and duration of melasma, and a χ² test was applied to compare efficacy in stratified groups (P≤.05).

Results

Sixty patients were enrolled in the study. Of them, 17 (28.33%) were male, and 43 (71.67%) were female (2:5 ratio). They ranged in age from 20 to 45 years (mean [SD], 31.93 [6.26] years). Thirty-seven patients (61.67%) were aged 31 to 45 years of age (Table 1). The mean (SD) duration of disease was 10.18 (2.10) months. The response to TA was recorded based on patient distribution according to the site of melasma as well as history of diabetes mellitus and hypertension.

Topical TA was found to be efficacious for melasma in 50 (83.33%) patients. The mean (SD) baseline and week 12 MASI scores were 23.15 (5.02) and 12.71 (4.10)(P<.0001), respectively (Table 2). The stratification of efficacy with respect to age, sex, duration of melasma, site of melasma, and history of diabetes mellitus or hypertension is shown in the eTable. The site of melasma was significant with respect to stratification of efficacy. On the forehead, TA was found to be efficacious in 11 patients and nonefficacious in 0 patients (P=.036). In the malar region, it was efficacious in 16 patients and nonefficacious in 1 patient (P=.036). Finally, on the chin, it was efficacious in 23 patients and nonefficacious in 9 patients (P=.036).

Comment

Melasma Presentation and Development—Melasma is a chronic skin condition that more often affects patients with darker skin types. This condition is characterized by hyperpigmentation of skin that is directly exposed to the sun, such as the cheek, nose, forehead, and above the upper lip.¹⁷ Although the mechanism behind how melasma develops is unknown, one theory suggests that UV light can lead to increased plasmin in keratinocytes.¹⁸ This increased plasmin will thereby increase the arachidonic acid and α-MSH, leading to the observed uneven hyperpigmentation that is notable in melasma. Melasma is common in patients using oral contraceptives or expired cosmetic drugs; in those who are pregnant; and in those with liver dysfunction.¹⁸ Melasma has a negative impact on patients’ quality of life because of substantial psychological and social distress. Thus, finding an accessible treatment is imperative.¹⁹

Melasma Management—The most common treatments for melasma have been topical bleaching agents and photoprotection. Combination therapy options include chemical peels, dermabrasion, and laser treatments, though they present with limited efficacy.^17,20 Because melasma focuses on pigmentation correction, topical treatments work to disturb melanocyte pigment production at the enzymatic level.²¹ Tyrosinase is rate limiting in melanin production, as it converts L-tyrosinase to L-3,4-dihydroxyphenylalanine, using copper to interact with L-3,4-dihydroxyphenylalanine as a cofactor in the active site.²² Therefore, tyrosine is a major target for many drugs that have been developed for melasma to decrease melaninization.²¹

Recently, research has focused on the effects of topical, intradermal, and oral TA for melasma.¹⁷ Tranexamic acid most commonly has been used in medicine as a fibrinolytic agent because of its antiplasmin properties. It has been hypothesized that TA can inhibit the release of paracrine melanogenic factors that normally act to stimulate melanocytes.¹⁷ Although studies have supported the safety and efficacy of TA, there remains a lack of clinical studies that are sufficiently powered. No definitive consensus on the use of TA for melasma currently exists, which indicates the need for large-scale, randomized, controlled trials.²³

One trial (N=25) found that TA solution 5% achieved efficacy (>50% reduction in MASI score from baseline) in 86.1% of patients with melasma.²⁴ In another study (N=18), topical TA 5% achieved efficacy (>50% reduction in MASI score) in 86% of patients with melasma.²⁵

Melasma Comorbidities—To determine if certain comorbidities, such as diabetes mellitus or hypertension, influenced the progression of melasma, we stratified the efficacy results for patients with these 2 comorbidities, which showed no significant difference (P=.794 and P=.101, respectively). Thus, the relatively higher prevalence of diabetes mellitus (16 patients) and hypertension (11 patients) did not contribute to the efficacy of TA in lowering MASI scores over the 12-week period, which supports the findings of Doolan and Gupta,²⁶ who investigated the endocrinologic conditions associated with melasma and found no such association with diabetes mellitus or hypertension.

TA Formulations for Melasma—The efficacy of topical TA has been explored in several studies. Six studies with sample sizes of 13 to 50 patients each showed statistically significant differences in MASI scores between baseline and following TA treatment (P<.001).^27-32 Several formulations and regimens were utilized, including TA cream 3% for 12 weeks, TA gel 5% for 12 weeks, TA solution 3% for 12 weeks, TA liposome 5% for 12 weeks, and TA solution 2% for 12 weeks.¹⁸ Additionally, these studies found TA to be effective in limiting dyschromia and decreasing MASI scores. There were no statistically significant differences between formulations and method of application. Topical TA has been found to be just as effective as other treatments for melasma, including intradermal TA injections, topical hydroquinone, and a combination of topical hydroquinone and dexamethasone.¹⁸

Further study of the efficacy of intradermal TA is necessary because many human trials have lacked statistical significance or a control group. Lee et al³² conducted a trial of 100 female patients who received weekly intradermal TA microinjections for 12 weeks. After 8 and 12 weeks, MASI scores decreased significantly (P<.01).³² Similarly, Badran et al³³ observed 60 female patients in 3 trial groups: group A received TA (4 mg/mL) intradermal injections every 2 weeks, group B received TA (10 mg/mL) intradermal injections every 2 weeks, and group C received TA cream 10% twice daily. Although all groups showed improvement in MASI, group B, which had the highest intradermal TA concentration, exhibited the most improvement. Thus, it was determined that intradermal application led to better results, but the cream was still effective.³³

Saki et al³⁴ conducted a randomized, split-face trial of 37 patients comparing the efficacy of intradermal TA and topical hydroquinone. Each group was treated with either monthly intradermal TA injections or nightly hydroquinone for 3 months. After 4 weeks of treatment, TA initially had a greater improvement. However, after 20 weeks, the overall changes were not significant between the 2 groups.³⁴ Pazyar et al³⁵ conducted a randomized, split-face trial of 49 patients comparing the efficacy of intradermal TA and hydroquinone cream. After 24 weeks of biweekly TA injections or twice-daily hydroquinone, there were no statistically significant differences in the decreased MASI scores between treatments.³⁵ Additional large, double-blind, controlled trials are needed to thoroughly assess the role of intradermal TA in comparison to its treatment counterpart of hydroquinone.

Ebrahimi and Naeini²⁹ conducted a 12-week, double-blind, split-phase trial of 50 Iranian melasma patients, which showed that 27.3% of patients rated the improvement in melasma as excellent, 42.4% as good, and 30.3% as fair after using TA solution 3%. Wu et al³⁶ also showed a total melasma improvement rate of 80.9% in 256 patients with long-term oral use of TA. In a study by Kim et al³¹ (N=245), the mean MASI score considerably decreased after topical TA use, with a total response rate of 95.6%. In another study, Atefi et al³⁷ presented significantly increased levels of satisfaction in patients treated with topical TA 5% vs hydroquinone (P=.015).

Melasma in Patients With Darker Skin Types—Special attention must be given to choosing the appropriate medication in melasma patients with darker skin types, as there is an increased risk for postinflammatory hyperpigmentation. Currently, few randomized controlled trials exist that fulfill the criteria of evaluating pharmacologic options for patients with melasma, and even fewer studies solely focus on patients with darker skin types.³⁸ In addition to treatment advances, patients must be educated on the need to avoid sun exposure when possible or to use photoprotection, especially in the South Asian region, where these practices rarely are taught. Our study provided a unique analysis regarding the efficacy of TA solution 5% for the treatment of melasma in patients of South Asian descent. Clinicians can use these findings as a foundation for treating all patients with melasma but particularly those with darker skin types.

Study Limitations—Our study consisted of 60 patients; although our study had more patients than similar trials, larger studies are needed. Additionally, other variables were excluded from our analysis, such as comorbidities beyond diabetes mellitus and hypertension.

Conclusion

This study contributes to the growing field of melasma therapeutics by evaluating the efficacy of using TA solution 5% for the treatment of melasma in South Asian patients with darker skin types. Clinicians may use our study to broaden their treatment options for a common condition while also addressing the lack of clinical options for patients with darker skin types. Further studies investigating the effectiveness of TA in large clinical trials in humans are warranted to understand the efficacy and the risk for any complications.

Melasma is a complex, long-lasting, acquired dermatologic pigmentation disorder resulting in grey-brown patches that last for more than 3 months. Sun-exposed areas including the nose, cheeks, forehead, and forearms are most likely to be affected.¹ In Southeast Asia, 0.25% to 4% of the population affected by melasma is aged 30 to 40 years.² In particular, melasma is a concern among pregnant women due to increased levels of melanocyte-stimulating hormones (MSHs) and is impacted by genetics, hormonal influence, and exposure to UV light.^3,4 In Pakistan, approximately 46% of women are affected by melasma during pregnancy.^2,5 Although few studies have focused on the clinical approaches to melasma in darker skin types, it continues to disproportionately affect the skin of color population.⁴

The areas of hyperpigmentation seen in melasma exhibit increased deposition of melanin in the epidermis and dermis, but melanocytes are not elevated. However, in areas of hyperpigmentation, the melanocytes are larger and more dendritic and demonstrate an increased level of melanogenesis.⁶ During pregnancy, especially in the third trimester, elevated levels of estrogen, progesterone, and MSH often are found in association with melasma.⁷ Tyrosinase (TYR) activity increases and cellular proliferation is reduced after treatment of melanocytes in culture with β-estradiol.⁸ Sex steroids increase transcription of genes encoding melanogenic enzymes in normal human melanocytes, especially TYR.⁹ These results are consistent with the notable increases in melanin synthesis and TYR activity reported for normal human melanocytes under similar conditions in culture.¹⁰ Because melanocytes contain both cytosolic and nuclear estrogen receptors, melanocytes in patients with melasma may be inherently more sensitive to the stimulatory effects of estrogens and possibly other steroid hormones.¹¹

The current treatment options for melasma have varying levels of success and include topical depigmenting agents such as hydroquinone, tretinoin, azelaic acid, kojic acid, and corticosteroids; dermabrasion; and chemical peels.^12-14 Chemical peels with glycolic acid, salicylic acid, lactic acid, trichloroacetic acid, and phenol, as well as laser therapy, are reliable management options.^13,14 Traditionally, melasma has been treated with a combination of modalities along with photoprotection and trigger avoidance.¹²

The efficacy and safety of the available therapies for melasma are still controversial and require further exploration. In recent years, off-label tranexamic acid (TA) has emerged as a potential therapy for melasma. Although the mechanism of action remains unclear, TA may inhibit melanin synthesis by blocking the interaction between melanocytes and keratinocytes.¹⁵ Tranexamic acid also may reverse the abnormal dermal changes associated with melasma by inhibiting melanogenesis and angiogenesis.¹⁶

Although various therapeutic options exist for melasma, the search for a reliable option in patients with darker skin types continues.¹³ We sought to evaluate the efficacy of TA solution 5% in reducing the severity of melasma in South Asian patients, thereby improving patient outcomes and maximizing patient satisfaction. Topical TA is inexpensive and readily accessible and does not cause systemic side effects. These qualities make it a promising treatment compared to traditional therapies.

Methods

We conducted a randomized controlled trial at Rawalpindi Medical Institute (Punjab, Pakistan). The researchers obtained informed consent for all enrolled patients. Cases were sampled from the original patient population seen at the office using nonprobability consecutive sampling. The sample size was calculated with a 95% CI, margin of error of 9%, and expected percentage of efficacy of 86.1% by using TA solution 5%. South Asian male and female patients aged 20 to 45 years with melasma were included in the analysis. Patients were excluded if they were already taking TA, oral contraceptive pills, or photosensitizing drugs (eg, nonsteroidal anti-inflammatory drugs, tetracyclines, phenytoin, carbamazepine); were pregnant; had chronic kidney disease (creatinine >2.0 mg/dL); had cardiac abnormalities (abnormal electrocardiogram); had hematologic disorders (international normalized ratio >2); or had received another melasma treatment within the last 3 to 6 months.

All enrolled patients underwent a detailed history and physical examination. Patient demographics were subsequently noted, including age, sex, history of diabetes mellitus or hypertension, and duration of melasma. The melasma area and severity index (MASI) score of each patient was calculated at baseline, and a corresponding photograph was taken.

The topical solution was prepared with 5 g of TA dissolved in 10 cc of ethanol at 96 °F, 10 cc of 1,3-butanediol, and distilled water up to 100 cc. The TA solution was applied to the affected areas once daily by the patient for 12 weeks. Each application covered the affected areas completely. Patients were instructed to apply sunscreen with sun protection factor 60 to those same areas for UV protection after 15 minutes of TA application. Biweekly follow-ups were scheduled during the trial, and the MASI score was recorded at these visits. If the mean MASI score was reduced by half after 12 weeks of treatment, then the treatment was considered efficacious with a 95% CI.

The percentage reduction from baseline was calculated as follows: percentage reduction=(baseline score– follow-up score)/baseline score×100.

Statistical Analysis—Data were analyzed in SPSS Statistics 25 (IBM). The quantitative variables of age, duration of melasma, and body mass index were presented as mean (SD). Qualitative variables such as sex, history of diabetes mellitus or hypertension, site of melasma, and efficacy were presented as frequencies and percentages. Mean MASI scores at baseline and 12 weeks posttreatment were compared using a paired t test (P≤.05). Data were stratified for age, sex, history of diabetes mellitus or hypertension, site of melasma, and duration of melasma, and a χ² test was applied to compare efficacy in stratified groups (P≤.05).

Results

Sixty patients were enrolled in the study. Of them, 17 (28.33%) were male, and 43 (71.67%) were female (2:5 ratio). They ranged in age from 20 to 45 years (mean [SD], 31.93 [6.26] years). Thirty-seven patients (61.67%) were aged 31 to 45 years of age (Table 1). The mean (SD) duration of disease was 10.18 (2.10) months. The response to TA was recorded based on patient distribution according to the site of melasma as well as history of diabetes mellitus and hypertension.

Topical TA was found to be efficacious for melasma in 50 (83.33%) patients. The mean (SD) baseline and week 12 MASI scores were 23.15 (5.02) and 12.71 (4.10)(P<.0001), respectively (Table 2). The stratification of efficacy with respect to age, sex, duration of melasma, site of melasma, and history of diabetes mellitus or hypertension is shown in the eTable. The site of melasma was significant with respect to stratification of efficacy. On the forehead, TA was found to be efficacious in 11 patients and nonefficacious in 0 patients (P=.036). In the malar region, it was efficacious in 16 patients and nonefficacious in 1 patient (P=.036). Finally, on the chin, it was efficacious in 23 patients and nonefficacious in 9 patients (P=.036).

Comment

Melasma Presentation and Development—Melasma is a chronic skin condition that more often affects patients with darker skin types. This condition is characterized by hyperpigmentation of skin that is directly exposed to the sun, such as the cheek, nose, forehead, and above the upper lip.¹⁷ Although the mechanism behind how melasma develops is unknown, one theory suggests that UV light can lead to increased plasmin in keratinocytes.¹⁸ This increased plasmin will thereby increase the arachidonic acid and α-MSH, leading to the observed uneven hyperpigmentation that is notable in melasma. Melasma is common in patients using oral contraceptives or expired cosmetic drugs; in those who are pregnant; and in those with liver dysfunction.¹⁸ Melasma has a negative impact on patients’ quality of life because of substantial psychological and social distress. Thus, finding an accessible treatment is imperative.¹⁹

Melasma Management—The most common treatments for melasma have been topical bleaching agents and photoprotection. Combination therapy options include chemical peels, dermabrasion, and laser treatments, though they present with limited efficacy.^17,20 Because melasma focuses on pigmentation correction, topical treatments work to disturb melanocyte pigment production at the enzymatic level.²¹ Tyrosinase is rate limiting in melanin production, as it converts L-tyrosinase to L-3,4-dihydroxyphenylalanine, using copper to interact with L-3,4-dihydroxyphenylalanine as a cofactor in the active site.²² Therefore, tyrosine is a major target for many drugs that have been developed for melasma to decrease melaninization.²¹

Recently, research has focused on the effects of topical, intradermal, and oral TA for melasma.¹⁷ Tranexamic acid most commonly has been used in medicine as a fibrinolytic agent because of its antiplasmin properties. It has been hypothesized that TA can inhibit the release of paracrine melanogenic factors that normally act to stimulate melanocytes.¹⁷ Although studies have supported the safety and efficacy of TA, there remains a lack of clinical studies that are sufficiently powered. No definitive consensus on the use of TA for melasma currently exists, which indicates the need for large-scale, randomized, controlled trials.²³

One trial (N=25) found that TA solution 5% achieved efficacy (>50% reduction in MASI score from baseline) in 86.1% of patients with melasma.²⁴ In another study (N=18), topical TA 5% achieved efficacy (>50% reduction in MASI score) in 86% of patients with melasma.²⁵

Melasma Comorbidities—To determine if certain comorbidities, such as diabetes mellitus or hypertension, influenced the progression of melasma, we stratified the efficacy results for patients with these 2 comorbidities, which showed no significant difference (P=.794 and P=.101, respectively). Thus, the relatively higher prevalence of diabetes mellitus (16 patients) and hypertension (11 patients) did not contribute to the efficacy of TA in lowering MASI scores over the 12-week period, which supports the findings of Doolan and Gupta,²⁶ who investigated the endocrinologic conditions associated with melasma and found no such association with diabetes mellitus or hypertension.

TA Formulations for Melasma—The efficacy of topical TA has been explored in several studies. Six studies with sample sizes of 13 to 50 patients each showed statistically significant differences in MASI scores between baseline and following TA treatment (P<.001).^27-32 Several formulations and regimens were utilized, including TA cream 3% for 12 weeks, TA gel 5% for 12 weeks, TA solution 3% for 12 weeks, TA liposome 5% for 12 weeks, and TA solution 2% for 12 weeks.¹⁸ Additionally, these studies found TA to be effective in limiting dyschromia and decreasing MASI scores. There were no statistically significant differences between formulations and method of application. Topical TA has been found to be just as effective as other treatments for melasma, including intradermal TA injections, topical hydroquinone, and a combination of topical hydroquinone and dexamethasone.¹⁸

Further study of the efficacy of intradermal TA is necessary because many human trials have lacked statistical significance or a control group. Lee et al³² conducted a trial of 100 female patients who received weekly intradermal TA microinjections for 12 weeks. After 8 and 12 weeks, MASI scores decreased significantly (P<.01).³² Similarly, Badran et al³³ observed 60 female patients in 3 trial groups: group A received TA (4 mg/mL) intradermal injections every 2 weeks, group B received TA (10 mg/mL) intradermal injections every 2 weeks, and group C received TA cream 10% twice daily. Although all groups showed improvement in MASI, group B, which had the highest intradermal TA concentration, exhibited the most improvement. Thus, it was determined that intradermal application led to better results, but the cream was still effective.³³

Saki et al³⁴ conducted a randomized, split-face trial of 37 patients comparing the efficacy of intradermal TA and topical hydroquinone. Each group was treated with either monthly intradermal TA injections or nightly hydroquinone for 3 months. After 4 weeks of treatment, TA initially had a greater improvement. However, after 20 weeks, the overall changes were not significant between the 2 groups.³⁴ Pazyar et al³⁵ conducted a randomized, split-face trial of 49 patients comparing the efficacy of intradermal TA and hydroquinone cream. After 24 weeks of biweekly TA injections or twice-daily hydroquinone, there were no statistically significant differences in the decreased MASI scores between treatments.³⁵ Additional large, double-blind, controlled trials are needed to thoroughly assess the role of intradermal TA in comparison to its treatment counterpart of hydroquinone.

Ebrahimi and Naeini²⁹ conducted a 12-week, double-blind, split-phase trial of 50 Iranian melasma patients, which showed that 27.3% of patients rated the improvement in melasma as excellent, 42.4% as good, and 30.3% as fair after using TA solution 3%. Wu et al³⁶ also showed a total melasma improvement rate of 80.9% in 256 patients with long-term oral use of TA. In a study by Kim et al³¹ (N=245), the mean MASI score considerably decreased after topical TA use, with a total response rate of 95.6%. In another study, Atefi et al³⁷ presented significantly increased levels of satisfaction in patients treated with topical TA 5% vs hydroquinone (P=.015).

Melasma in Patients With Darker Skin Types—Special attention must be given to choosing the appropriate medication in melasma patients with darker skin types, as there is an increased risk for postinflammatory hyperpigmentation. Currently, few randomized controlled trials exist that fulfill the criteria of evaluating pharmacologic options for patients with melasma, and even fewer studies solely focus on patients with darker skin types.³⁸ In addition to treatment advances, patients must be educated on the need to avoid sun exposure when possible or to use photoprotection, especially in the South Asian region, where these practices rarely are taught. Our study provided a unique analysis regarding the efficacy of TA solution 5% for the treatment of melasma in patients of South Asian descent. Clinicians can use these findings as a foundation for treating all patients with melasma but particularly those with darker skin types.

Study Limitations—Our study consisted of 60 patients; although our study had more patients than similar trials, larger studies are needed. Additionally, other variables were excluded from our analysis, such as comorbidities beyond diabetes mellitus and hypertension.

Conclusion

This study contributes to the growing field of melasma therapeutics by evaluating the efficacy of using TA solution 5% for the treatment of melasma in South Asian patients with darker skin types. Clinicians may use our study to broaden their treatment options for a common condition while also addressing the lack of clinical options for patients with darker skin types. Further studies investigating the effectiveness of TA in large clinical trials in humans are warranted to understand the efficacy and the risk for any complications.

Melasma is a complex, long-lasting, acquired dermatologic pigmentation disorder resulting in grey-brown patches that last for more than 3 months. Sun-exposed areas including the nose, cheeks, forehead, and forearms are most likely to be affected.¹ In Southeast Asia, 0.25% to 4% of the population affected by melasma is aged 30 to 40 years.² In particular, melasma is a concern among pregnant women due to increased levels of melanocyte-stimulating hormones (MSHs) and is impacted by genetics, hormonal influence, and exposure to UV light.^3,4 In Pakistan, approximately 46% of women are affected by melasma during pregnancy.^2,5 Although few studies have focused on the clinical approaches to melasma in darker skin types, it continues to disproportionately affect the skin of color population.⁴

The areas of hyperpigmentation seen in melasma exhibit increased deposition of melanin in the epidermis and dermis, but melanocytes are not elevated. However, in areas of hyperpigmentation, the melanocytes are larger and more dendritic and demonstrate an increased level of melanogenesis.⁶ During pregnancy, especially in the third trimester, elevated levels of estrogen, progesterone, and MSH often are found in association with melasma.⁷ Tyrosinase (TYR) activity increases and cellular proliferation is reduced after treatment of melanocytes in culture with β-estradiol.⁸ Sex steroids increase transcription of genes encoding melanogenic enzymes in normal human melanocytes, especially TYR.⁹ These results are consistent with the notable increases in melanin synthesis and TYR activity reported for normal human melanocytes under similar conditions in culture.¹⁰ Because melanocytes contain both cytosolic and nuclear estrogen receptors, melanocytes in patients with melasma may be inherently more sensitive to the stimulatory effects of estrogens and possibly other steroid hormones.¹¹

The current treatment options for melasma have varying levels of success and include topical depigmenting agents such as hydroquinone, tretinoin, azelaic acid, kojic acid, and corticosteroids; dermabrasion; and chemical peels.^12-14 Chemical peels with glycolic acid, salicylic acid, lactic acid, trichloroacetic acid, and phenol, as well as laser therapy, are reliable management options.^13,14 Traditionally, melasma has been treated with a combination of modalities along with photoprotection and trigger avoidance.¹²

The efficacy and safety of the available therapies for melasma are still controversial and require further exploration. In recent years, off-label tranexamic acid (TA) has emerged as a potential therapy for melasma. Although the mechanism of action remains unclear, TA may inhibit melanin synthesis by blocking the interaction between melanocytes and keratinocytes.¹⁵ Tranexamic acid also may reverse the abnormal dermal changes associated with melasma by inhibiting melanogenesis and angiogenesis.¹⁶

Although various therapeutic options exist for melasma, the search for a reliable option in patients with darker skin types continues.¹³ We sought to evaluate the efficacy of TA solution 5% in reducing the severity of melasma in South Asian patients, thereby improving patient outcomes and maximizing patient satisfaction. Topical TA is inexpensive and readily accessible and does not cause systemic side effects. These qualities make it a promising treatment compared to traditional therapies.

Methods

We conducted a randomized controlled trial at Rawalpindi Medical Institute (Punjab, Pakistan). The researchers obtained informed consent for all enrolled patients. Cases were sampled from the original patient population seen at the office using nonprobability consecutive sampling. The sample size was calculated with a 95% CI, margin of error of 9%, and expected percentage of efficacy of 86.1% by using TA solution 5%. South Asian male and female patients aged 20 to 45 years with melasma were included in the analysis. Patients were excluded if they were already taking TA, oral contraceptive pills, or photosensitizing drugs (eg, nonsteroidal anti-inflammatory drugs, tetracyclines, phenytoin, carbamazepine); were pregnant; had chronic kidney disease (creatinine >2.0 mg/dL); had cardiac abnormalities (abnormal electrocardiogram); had hematologic disorders (international normalized ratio >2); or had received another melasma treatment within the last 3 to 6 months.

All enrolled patients underwent a detailed history and physical examination. Patient demographics were subsequently noted, including age, sex, history of diabetes mellitus or hypertension, and duration of melasma. The melasma area and severity index (MASI) score of each patient was calculated at baseline, and a corresponding photograph was taken.

The topical solution was prepared with 5 g of TA dissolved in 10 cc of ethanol at 96 °F, 10 cc of 1,3-butanediol, and distilled water up to 100 cc. The TA solution was applied to the affected areas once daily by the patient for 12 weeks. Each application covered the affected areas completely. Patients were instructed to apply sunscreen with sun protection factor 60 to those same areas for UV protection after 15 minutes of TA application. Biweekly follow-ups were scheduled during the trial, and the MASI score was recorded at these visits. If the mean MASI score was reduced by half after 12 weeks of treatment, then the treatment was considered efficacious with a 95% CI.

The percentage reduction from baseline was calculated as follows: percentage reduction=(baseline score– follow-up score)/baseline score×100.

Statistical Analysis—Data were analyzed in SPSS Statistics 25 (IBM). The quantitative variables of age, duration of melasma, and body mass index were presented as mean (SD). Qualitative variables such as sex, history of diabetes mellitus or hypertension, site of melasma, and efficacy were presented as frequencies and percentages. Mean MASI scores at baseline and 12 weeks posttreatment were compared using a paired t test (P≤.05). Data were stratified for age, sex, history of diabetes mellitus or hypertension, site of melasma, and duration of melasma, and a χ² test was applied to compare efficacy in stratified groups (P≤.05).

Results

Sixty patients were enrolled in the study. Of them, 17 (28.33%) were male, and 43 (71.67%) were female (2:5 ratio). They ranged in age from 20 to 45 years (mean [SD], 31.93 [6.26] years). Thirty-seven patients (61.67%) were aged 31 to 45 years of age (Table 1). The mean (SD) duration of disease was 10.18 (2.10) months. The response to TA was recorded based on patient distribution according to the site of melasma as well as history of diabetes mellitus and hypertension.

Topical TA was found to be efficacious for melasma in 50 (83.33%) patients. The mean (SD) baseline and week 12 MASI scores were 23.15 (5.02) and 12.71 (4.10)(P<.0001), respectively (Table 2). The stratification of efficacy with respect to age, sex, duration of melasma, site of melasma, and history of diabetes mellitus or hypertension is shown in the eTable. The site of melasma was significant with respect to stratification of efficacy. On the forehead, TA was found to be efficacious in 11 patients and nonefficacious in 0 patients (P=.036). In the malar region, it was efficacious in 16 patients and nonefficacious in 1 patient (P=.036). Finally, on the chin, it was efficacious in 23 patients and nonefficacious in 9 patients (P=.036).

Comment

Melasma Presentation and Development—Melasma is a chronic skin condition that more often affects patients with darker skin types. This condition is characterized by hyperpigmentation of skin that is directly exposed to the sun, such as the cheek, nose, forehead, and above the upper lip.¹⁷ Although the mechanism behind how melasma develops is unknown, one theory suggests that UV light can lead to increased plasmin in keratinocytes.¹⁸ This increased plasmin will thereby increase the arachidonic acid and α-MSH, leading to the observed uneven hyperpigmentation that is notable in melasma. Melasma is common in patients using oral contraceptives or expired cosmetic drugs; in those who are pregnant; and in those with liver dysfunction.¹⁸ Melasma has a negative impact on patients’ quality of life because of substantial psychological and social distress. Thus, finding an accessible treatment is imperative.¹⁹

Melasma Management—The most common treatments for melasma have been topical bleaching agents and photoprotection. Combination therapy options include chemical peels, dermabrasion, and laser treatments, though they present with limited efficacy.^17,20 Because melasma focuses on pigmentation correction, topical treatments work to disturb melanocyte pigment production at the enzymatic level.²¹ Tyrosinase is rate limiting in melanin production, as it converts L-tyrosinase to L-3,4-dihydroxyphenylalanine, using copper to interact with L-3,4-dihydroxyphenylalanine as a cofactor in the active site.²² Therefore, tyrosine is a major target for many drugs that have been developed for melasma to decrease melaninization.²¹

Recently, research has focused on the effects of topical, intradermal, and oral TA for melasma.¹⁷ Tranexamic acid most commonly has been used in medicine as a fibrinolytic agent because of its antiplasmin properties. It has been hypothesized that TA can inhibit the release of paracrine melanogenic factors that normally act to stimulate melanocytes.¹⁷ Although studies have supported the safety and efficacy of TA, there remains a lack of clinical studies that are sufficiently powered. No definitive consensus on the use of TA for melasma currently exists, which indicates the need for large-scale, randomized, controlled trials.²³

One trial (N=25) found that TA solution 5% achieved efficacy (>50% reduction in MASI score from baseline) in 86.1% of patients with melasma.²⁴ In another study (N=18), topical TA 5% achieved efficacy (>50% reduction in MASI score) in 86% of patients with melasma.²⁵

Melasma Comorbidities—To determine if certain comorbidities, such as diabetes mellitus or hypertension, influenced the progression of melasma, we stratified the efficacy results for patients with these 2 comorbidities, which showed no significant difference (P=.794 and P=.101, respectively). Thus, the relatively higher prevalence of diabetes mellitus (16 patients) and hypertension (11 patients) did not contribute to the efficacy of TA in lowering MASI scores over the 12-week period, which supports the findings of Doolan and Gupta,²⁶ who investigated the endocrinologic conditions associated with melasma and found no such association with diabetes mellitus or hypertension.

TA Formulations for Melasma—The efficacy of topical TA has been explored in several studies. Six studies with sample sizes of 13 to 50 patients each showed statistically significant differences in MASI scores between baseline and following TA treatment (P<.001).^27-32 Several formulations and regimens were utilized, including TA cream 3% for 12 weeks, TA gel 5% for 12 weeks, TA solution 3% for 12 weeks, TA liposome 5% for 12 weeks, and TA solution 2% for 12 weeks.¹⁸ Additionally, these studies found TA to be effective in limiting dyschromia and decreasing MASI scores. There were no statistically significant differences between formulations and method of application. Topical TA has been found to be just as effective as other treatments for melasma, including intradermal TA injections, topical hydroquinone, and a combination of topical hydroquinone and dexamethasone.¹⁸

Further study of the efficacy of intradermal TA is necessary because many human trials have lacked statistical significance or a control group. Lee et al³² conducted a trial of 100 female patients who received weekly intradermal TA microinjections for 12 weeks. After 8 and 12 weeks, MASI scores decreased significantly (P<.01).³² Similarly, Badran et al³³ observed 60 female patients in 3 trial groups: group A received TA (4 mg/mL) intradermal injections every 2 weeks, group B received TA (10 mg/mL) intradermal injections every 2 weeks, and group C received TA cream 10% twice daily. Although all groups showed improvement in MASI, group B, which had the highest intradermal TA concentration, exhibited the most improvement. Thus, it was determined that intradermal application led to better results, but the cream was still effective.³³

Saki et al³⁴ conducted a randomized, split-face trial of 37 patients comparing the efficacy of intradermal TA and topical hydroquinone. Each group was treated with either monthly intradermal TA injections or nightly hydroquinone for 3 months. After 4 weeks of treatment, TA initially had a greater improvement. However, after 20 weeks, the overall changes were not significant between the 2 groups.³⁴ Pazyar et al³⁵ conducted a randomized, split-face trial of 49 patients comparing the efficacy of intradermal TA and hydroquinone cream. After 24 weeks of biweekly TA injections or twice-daily hydroquinone, there were no statistically significant differences in the decreased MASI scores between treatments.³⁵ Additional large, double-blind, controlled trials are needed to thoroughly assess the role of intradermal TA in comparison to its treatment counterpart of hydroquinone.

Ebrahimi and Naeini²⁹ conducted a 12-week, double-blind, split-phase trial of 50 Iranian melasma patients, which showed that 27.3% of patients rated the improvement in melasma as excellent, 42.4% as good, and 30.3% as fair after using TA solution 3%. Wu et al³⁶ also showed a total melasma improvement rate of 80.9% in 256 patients with long-term oral use of TA. In a study by Kim et al³¹ (N=245), the mean MASI score considerably decreased after topical TA use, with a total response rate of 95.6%. In another study, Atefi et al³⁷ presented significantly increased levels of satisfaction in patients treated with topical TA 5% vs hydroquinone (P=.015).

Melasma in Patients With Darker Skin Types—Special attention must be given to choosing the appropriate medication in melasma patients with darker skin types, as there is an increased risk for postinflammatory hyperpigmentation. Currently, few randomized controlled trials exist that fulfill the criteria of evaluating pharmacologic options for patients with melasma, and even fewer studies solely focus on patients with darker skin types.³⁸ In addition to treatment advances, patients must be educated on the need to avoid sun exposure when possible or to use photoprotection, especially in the South Asian region, where these practices rarely are taught. Our study provided a unique analysis regarding the efficacy of TA solution 5% for the treatment of melasma in patients of South Asian descent. Clinicians can use these findings as a foundation for treating all patients with melasma but particularly those with darker skin types.

Study Limitations—Our study consisted of 60 patients; although our study had more patients than similar trials, larger studies are needed. Additionally, other variables were excluded from our analysis, such as comorbidities beyond diabetes mellitus and hypertension.

Conclusion

This study contributes to the growing field of melasma therapeutics by evaluating the efficacy of using TA solution 5% for the treatment of melasma in South Asian patients with darker skin types. Clinicians may use our study to broaden their treatment options for a common condition while also addressing the lack of clinical options for patients with darker skin types. Further studies investigating the effectiveness of TA in large clinical trials in humans are warranted to understand the efficacy and the risk for any complications.

The Diagnosis: Eccrine Poroma

Histopathology demonstrated epidermal thickening, epidermal protrusions, a well-defined mass of tumor cells that extended from the epidermis down to the dermis, and luminal structures. Poroid cells and ovoid nuclei with basophilic cytoplasm also were evident (Figure 1). Dermoscopy showed papillomatous growth, milky-red areas, and dotted vessels (Figure 2). Reflectance confocal microscopy (RCM) at the spinous layer showed hyporefractile, dark, roundish lumina surrounded by keratinocytes (Figure 3). Based on the histologic, dermoscopic, and RCM findings, our patient was diagnosed with eccrine poroma.

Goldman et al¹ first described poroma in 1956. Poromas, which include eccrine poroma, are a group of benign cutaneous neoplasms arising from the terminal eccrine or apocrine sweat gland ducts.² Histologically, poroid cells appear as cuboidal keratinocytes with monomorphous ovoid nuclei and discrete nucleoli.³ They usually appear as nodules or plaques with colors varying from flesh colored to red, brown, or bluish, and they clinically mimic several benign and malignant skin tumors. The differential diagnosis may include keratoacanthoma, plantar wart, verrucous carcinoma, basal cell carcinoma, and squamous cell carcinoma. Poromas can be of eccrine or apocrine origin.⁴ They also belong to a broad group of neoplasms, including nodular hidradenomas, clear cell hidradenomas, hidroacanthoma simplex, dermal duct tumors, and hidradenomas.⁵ Four subtypes—poroma, poroid hidradenoma, hidroacanthoma simplex, and dermal duct tumor—have been documented.⁶ Because poromas have nonspecific and variable clinical presentations, they often are misdiagnosed as other skin neoplasms, and differentiation may be difficult. For example, some cases of poroma present with follicular, sebaceous, and/or apocrine differentiation, leading to difficulty in diagnosis.

Characteristic features of eccrine poroma seen on dermoscopy and RCM have the potential to aid in the diagnosis compared to histopathology. Marchetti et al⁷ proposed 4 patterns of characteristic dermoscopic findings. Pattern 1 refers to the classic description with bleeding spots, a structureless yellow appearance, milkyred globules, and branched vessels. Patterns 2 and 3 simulate basal cell carcinoma, dermal nevus, or vascular tumors. Pattern 4 refers to tumors that are large in size and resemble keratinizing neoplasms.⁷ Brugués et al⁸ described poromas with the following RCM findings: an atypical honeycomb shape that was well separated from the normal epithelium, hyporefractile nests with atypical cells, lack of palisading, and dark holes. One study described RCM parameters as cords without palisading, dark holes, prominent vascularization, and abundant stroma—findings that were positively associated with poroma in a univariate analysis. These findings assist in distinguishing poromas from other conditions in the differential diagnosis.⁹

There is a substantial overlap in clinical appearance with malignant conditions, including basal cell carcinoma, squamous cell carcinoma, cutaneous metastases, and Paget disease; therefore, the use of dermoscopy and RCM may be helpful in the diagnosis and recognition of specific features, as well as the corresponding patterns of poroma. Poromas commonly display vascularized features due to the variability of dermoscopic patterns of eccrine poroma, and further studies are required to establish the specificity of vascularized features.

Acral lesions are more likely to show the classic clinical features of erythema and exophytic growth. A case of a collision tumor with the verrucous changes of poroma, seborrheic keratosis, and viral wart has been described.10 The verrucous changes may lead to misdiagnosis as plantar warts or other neoplasms. Clinicians also should consider conditions that are induced by friction or trauma. In our patient, dermoscopy and RCM aided in the diagnosis of eccrine poroma due to the interference of prominent overlying verrucous changes.

Treatment of poroma is optional. Deeper lesions can be treated with surgical excision, and superficial lesions may be treated with electrosurgical destruction. Our patient was treated with surgical excision followed by repair of the surgical defect with a double V-Y flap.

The Diagnosis: Eccrine Poroma

Histopathology demonstrated epidermal thickening, epidermal protrusions, a well-defined mass of tumor cells that extended from the epidermis down to the dermis, and luminal structures. Poroid cells and ovoid nuclei with basophilic cytoplasm also were evident (Figure 1). Dermoscopy showed papillomatous growth, milky-red areas, and dotted vessels (Figure 2). Reflectance confocal microscopy (RCM) at the spinous layer showed hyporefractile, dark, roundish lumina surrounded by keratinocytes (Figure 3). Based on the histologic, dermoscopic, and RCM findings, our patient was diagnosed with eccrine poroma.

Goldman et al¹ first described poroma in 1956. Poromas, which include eccrine poroma, are a group of benign cutaneous neoplasms arising from the terminal eccrine or apocrine sweat gland ducts.² Histologically, poroid cells appear as cuboidal keratinocytes with monomorphous ovoid nuclei and discrete nucleoli.³ They usually appear as nodules or plaques with colors varying from flesh colored to red, brown, or bluish, and they clinically mimic several benign and malignant skin tumors. The differential diagnosis may include keratoacanthoma, plantar wart, verrucous carcinoma, basal cell carcinoma, and squamous cell carcinoma. Poromas can be of eccrine or apocrine origin.⁴ They also belong to a broad group of neoplasms, including nodular hidradenomas, clear cell hidradenomas, hidroacanthoma simplex, dermal duct tumors, and hidradenomas.⁵ Four subtypes—poroma, poroid hidradenoma, hidroacanthoma simplex, and dermal duct tumor—have been documented.⁶ Because poromas have nonspecific and variable clinical presentations, they often are misdiagnosed as other skin neoplasms, and differentiation may be difficult. For example, some cases of poroma present with follicular, sebaceous, and/or apocrine differentiation, leading to difficulty in diagnosis.

Characteristic features of eccrine poroma seen on dermoscopy and RCM have the potential to aid in the diagnosis compared to histopathology. Marchetti et al⁷ proposed 4 patterns of characteristic dermoscopic findings. Pattern 1 refers to the classic description with bleeding spots, a structureless yellow appearance, milkyred globules, and branched vessels. Patterns 2 and 3 simulate basal cell carcinoma, dermal nevus, or vascular tumors. Pattern 4 refers to tumors that are large in size and resemble keratinizing neoplasms.⁷ Brugués et al⁸ described poromas with the following RCM findings: an atypical honeycomb shape that was well separated from the normal epithelium, hyporefractile nests with atypical cells, lack of palisading, and dark holes. One study described RCM parameters as cords without palisading, dark holes, prominent vascularization, and abundant stroma—findings that were positively associated with poroma in a univariate analysis. These findings assist in distinguishing poromas from other conditions in the differential diagnosis.⁹

There is a substantial overlap in clinical appearance with malignant conditions, including basal cell carcinoma, squamous cell carcinoma, cutaneous metastases, and Paget disease; therefore, the use of dermoscopy and RCM may be helpful in the diagnosis and recognition of specific features, as well as the corresponding patterns of poroma. Poromas commonly display vascularized features due to the variability of dermoscopic patterns of eccrine poroma, and further studies are required to establish the specificity of vascularized features.

Acral lesions are more likely to show the classic clinical features of erythema and exophytic growth. A case of a collision tumor with the verrucous changes of poroma, seborrheic keratosis, and viral wart has been described.10 The verrucous changes may lead to misdiagnosis as plantar warts or other neoplasms. Clinicians also should consider conditions that are induced by friction or trauma. In our patient, dermoscopy and RCM aided in the diagnosis of eccrine poroma due to the interference of prominent overlying verrucous changes.

Treatment of poroma is optional. Deeper lesions can be treated with surgical excision, and superficial lesions may be treated with electrosurgical destruction. Our patient was treated with surgical excision followed by repair of the surgical defect with a double V-Y flap.

The Diagnosis: Eccrine Poroma

Histopathology demonstrated epidermal thickening, epidermal protrusions, a well-defined mass of tumor cells that extended from the epidermis down to the dermis, and luminal structures. Poroid cells and ovoid nuclei with basophilic cytoplasm also were evident (Figure 1). Dermoscopy showed papillomatous growth, milky-red areas, and dotted vessels (Figure 2). Reflectance confocal microscopy (RCM) at the spinous layer showed hyporefractile, dark, roundish lumina surrounded by keratinocytes (Figure 3). Based on the histologic, dermoscopic, and RCM findings, our patient was diagnosed with eccrine poroma.

Goldman et al¹ first described poroma in 1956. Poromas, which include eccrine poroma, are a group of benign cutaneous neoplasms arising from the terminal eccrine or apocrine sweat gland ducts.² Histologically, poroid cells appear as cuboidal keratinocytes with monomorphous ovoid nuclei and discrete nucleoli.³ They usually appear as nodules or plaques with colors varying from flesh colored to red, brown, or bluish, and they clinically mimic several benign and malignant skin tumors. The differential diagnosis may include keratoacanthoma, plantar wart, verrucous carcinoma, basal cell carcinoma, and squamous cell carcinoma. Poromas can be of eccrine or apocrine origin.⁴ They also belong to a broad group of neoplasms, including nodular hidradenomas, clear cell hidradenomas, hidroacanthoma simplex, dermal duct tumors, and hidradenomas.⁵ Four subtypes—poroma, poroid hidradenoma, hidroacanthoma simplex, and dermal duct tumor—have been documented.⁶ Because poromas have nonspecific and variable clinical presentations, they often are misdiagnosed as other skin neoplasms, and differentiation may be difficult. For example, some cases of poroma present with follicular, sebaceous, and/or apocrine differentiation, leading to difficulty in diagnosis.

Characteristic features of eccrine poroma seen on dermoscopy and RCM have the potential to aid in the diagnosis compared to histopathology. Marchetti et al⁷ proposed 4 patterns of characteristic dermoscopic findings. Pattern 1 refers to the classic description with bleeding spots, a structureless yellow appearance, milkyred globules, and branched vessels. Patterns 2 and 3 simulate basal cell carcinoma, dermal nevus, or vascular tumors. Pattern 4 refers to tumors that are large in size and resemble keratinizing neoplasms.⁷ Brugués et al⁸ described poromas with the following RCM findings: an atypical honeycomb shape that was well separated from the normal epithelium, hyporefractile nests with atypical cells, lack of palisading, and dark holes. One study described RCM parameters as cords without palisading, dark holes, prominent vascularization, and abundant stroma—findings that were positively associated with poroma in a univariate analysis. These findings assist in distinguishing poromas from other conditions in the differential diagnosis.⁹

There is a substantial overlap in clinical appearance with malignant conditions, including basal cell carcinoma, squamous cell carcinoma, cutaneous metastases, and Paget disease; therefore, the use of dermoscopy and RCM may be helpful in the diagnosis and recognition of specific features, as well as the corresponding patterns of poroma. Poromas commonly display vascularized features due to the variability of dermoscopic patterns of eccrine poroma, and further studies are required to establish the specificity of vascularized features.

Acral lesions are more likely to show the classic clinical features of erythema and exophytic growth. A case of a collision tumor with the verrucous changes of poroma, seborrheic keratosis, and viral wart has been described.10 The verrucous changes may lead to misdiagnosis as plantar warts or other neoplasms. Clinicians also should consider conditions that are induced by friction or trauma. In our patient, dermoscopy and RCM aided in the diagnosis of eccrine poroma due to the interference of prominent overlying verrucous changes.

Treatment of poroma is optional. Deeper lesions can be treated with surgical excision, and superficial lesions may be treated with electrosurgical destruction. Our patient was treated with surgical excision followed by repair of the surgical defect with a double V-Y flap.

There have been several recent developments in the treatment of B-cell lymphoma; however, one of the most significant advances has been the development of chimeric antigen receptor (CAR) T-cell therapy. CAR T-cell therapy is a type of personalized immunotherapy that can help cure some people with aggressive non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), the most common form of aggressive NHL. CAR T-cell therapy has revolutionized the treatment of hematologic malignancies over the past 5 years, with impressive response rates and durable remissions for patients who previously had no viable options. This strategy is highly effective in patients with relapsed/refractory DLBCL, as well as mantle cell lymphoma, follicular lymphoma, acute lymphoblastic leukemia (ALL), and multiple myeloma, as evidenced by recent regulatory approvals. 

The initial products, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel)— both FDA approved in 2017—involve administration of autologous T-cells programmed to express a CAR targeting the B-cell marker CD19. 

In 2021, the FDA also approved lisocabtagene maraleucel (liso-cel), a new CAR T-cell therapy for the treatment of adults with relapsed or refractory (nonresponsive) large B-cell lymphoma (LBCL) have been treated with at least 2 prior lines of therapy. These products have design differences, including differences in the costimulatory domain, mechanism of gene/transgene delivery, ability for cryopreservation, and need for T-cell selection.

The CAR T-cell therapy axi-cel demonstrated superior results in the ZUMA-7 clinical trial, which compared CAR T-cell therapy directly to traditional chemotherapy with intended autologous stem cell transplant (ASCT). About 55% of patients were still alive 4 years after receiving axi-cel, compared with 46% of those who initially received the standard treatment for relapsed disease. Based on these results, axi-cel is now the preferred treatment for people whose DLBCL has recurred with 12 months of front-line treatment or who are resistant to standard initial treatment.

Additionally, the BELINDA trial was a randomized phase 3 trial that compared CAR T-cell therapy with liso-cel with second-line chemotherapy with planned ASCT. Like ZUMA-7, this study also demonstrated an improvement in progression-free survival (PFS) compared to standard treatment. As such, CAR T-cell therapy represents the new standard of care for second-line treatment in appropriate patients with refractory or early relapsing LBCL.

There have been several other recent studies on the use of CAR T-cell therapy for B-cell lymphoma. One study, published in Blood Advances (2023), found that receiving a greater number of therapies prior to CAR T-cell therapy is associated with poorer outcomes in patients with aggressive relapsed/refractory B-cell NHL. The study, which included 514 patients from 13 centers treated with CAR-T for aggressive B-cell NHL between 2015 and 2021, found that a greater number of lines of therapy before CAR-T apheresis and bridging therapy were predictive of inferior PFS and overall survival. 

Another study compared 2 CD19-targeting CAR T-cell treatments, axi-cel and tisa-cel, with ASCT in the second line setting for LBCL. The study found that axi-cel was superior to ASCT, with longer median event-free survival and a higher response rate. However, tisa-cel was not found to be superior to ASCT. Further studies will be needed to definitively characterize the relative benefits of CAR-T cell therapies and standard second-line treatments for different subgroups of patients with LBCL. 

An increasing number of effective targeted agents for DLBCL, including novel monoclonal antibodies (tafasitamab) and antibody-drug conjugates (polatuzumab vedotin and loncastuximab teserine), are being used in earlier lines of therapy. Additionally, 2 anti-CD20 bispecific antibodies (epcoritamab and glofitamab) have gained approval for relapsed/refractory DLBCL due to high response rates. Future studies will be needed to determine if treatment with these agents can produce durable remissions like that of CAR-T cell therapy.

There have been several recent developments in the treatment of B-cell lymphoma; however, one of the most significant advances has been the development of chimeric antigen receptor (CAR) T-cell therapy. CAR T-cell therapy is a type of personalized immunotherapy that can help cure some people with aggressive non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), the most common form of aggressive NHL. CAR T-cell therapy has revolutionized the treatment of hematologic malignancies over the past 5 years, with impressive response rates and durable remissions for patients who previously had no viable options. This strategy is highly effective in patients with relapsed/refractory DLBCL, as well as mantle cell lymphoma, follicular lymphoma, acute lymphoblastic leukemia (ALL), and multiple myeloma, as evidenced by recent regulatory approvals. 

The initial products, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel)— both FDA approved in 2017—involve administration of autologous T-cells programmed to express a CAR targeting the B-cell marker CD19. 

In 2021, the FDA also approved lisocabtagene maraleucel (liso-cel), a new CAR T-cell therapy for the treatment of adults with relapsed or refractory (nonresponsive) large B-cell lymphoma (LBCL) have been treated with at least 2 prior lines of therapy. These products have design differences, including differences in the costimulatory domain, mechanism of gene/transgene delivery, ability for cryopreservation, and need for T-cell selection.

The CAR T-cell therapy axi-cel demonstrated superior results in the ZUMA-7 clinical trial, which compared CAR T-cell therapy directly to traditional chemotherapy with intended autologous stem cell transplant (ASCT). About 55% of patients were still alive 4 years after receiving axi-cel, compared with 46% of those who initially received the standard treatment for relapsed disease. Based on these results, axi-cel is now the preferred treatment for people whose DLBCL has recurred with 12 months of front-line treatment or who are resistant to standard initial treatment.

Additionally, the BELINDA trial was a randomized phase 3 trial that compared CAR T-cell therapy with liso-cel with second-line chemotherapy with planned ASCT. Like ZUMA-7, this study also demonstrated an improvement in progression-free survival (PFS) compared to standard treatment. As such, CAR T-cell therapy represents the new standard of care for second-line treatment in appropriate patients with refractory or early relapsing LBCL.

There have been several other recent studies on the use of CAR T-cell therapy for B-cell lymphoma. One study, published in Blood Advances (2023), found that receiving a greater number of therapies prior to CAR T-cell therapy is associated with poorer outcomes in patients with aggressive relapsed/refractory B-cell NHL. The study, which included 514 patients from 13 centers treated with CAR-T for aggressive B-cell NHL between 2015 and 2021, found that a greater number of lines of therapy before CAR-T apheresis and bridging therapy were predictive of inferior PFS and overall survival. 

Another study compared 2 CD19-targeting CAR T-cell treatments, axi-cel and tisa-cel, with ASCT in the second line setting for LBCL. The study found that axi-cel was superior to ASCT, with longer median event-free survival and a higher response rate. However, tisa-cel was not found to be superior to ASCT. Further studies will be needed to definitively characterize the relative benefits of CAR-T cell therapies and standard second-line treatments for different subgroups of patients with LBCL. 

An increasing number of effective targeted agents for DLBCL, including novel monoclonal antibodies (tafasitamab) and antibody-drug conjugates (polatuzumab vedotin and loncastuximab teserine), are being used in earlier lines of therapy. Additionally, 2 anti-CD20 bispecific antibodies (epcoritamab and glofitamab) have gained approval for relapsed/refractory DLBCL due to high response rates. Future studies will be needed to determine if treatment with these agents can produce durable remissions like that of CAR-T cell therapy.

There have been several recent developments in the treatment of B-cell lymphoma; however, one of the most significant advances has been the development of chimeric antigen receptor (CAR) T-cell therapy. CAR T-cell therapy is a type of personalized immunotherapy that can help cure some people with aggressive non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), the most common form of aggressive NHL. CAR T-cell therapy has revolutionized the treatment of hematologic malignancies over the past 5 years, with impressive response rates and durable remissions for patients who previously had no viable options. This strategy is highly effective in patients with relapsed/refractory DLBCL, as well as mantle cell lymphoma, follicular lymphoma, acute lymphoblastic leukemia (ALL), and multiple myeloma, as evidenced by recent regulatory approvals. 

The initial products, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel)— both FDA approved in 2017—involve administration of autologous T-cells programmed to express a CAR targeting the B-cell marker CD19. 

In 2021, the FDA also approved lisocabtagene maraleucel (liso-cel), a new CAR T-cell therapy for the treatment of adults with relapsed or refractory (nonresponsive) large B-cell lymphoma (LBCL) have been treated with at least 2 prior lines of therapy. These products have design differences, including differences in the costimulatory domain, mechanism of gene/transgene delivery, ability for cryopreservation, and need for T-cell selection.

The CAR T-cell therapy axi-cel demonstrated superior results in the ZUMA-7 clinical trial, which compared CAR T-cell therapy directly to traditional chemotherapy with intended autologous stem cell transplant (ASCT). About 55% of patients were still alive 4 years after receiving axi-cel, compared with 46% of those who initially received the standard treatment for relapsed disease. Based on these results, axi-cel is now the preferred treatment for people whose DLBCL has recurred with 12 months of front-line treatment or who are resistant to standard initial treatment.

Additionally, the BELINDA trial was a randomized phase 3 trial that compared CAR T-cell therapy with liso-cel with second-line chemotherapy with planned ASCT. Like ZUMA-7, this study also demonstrated an improvement in progression-free survival (PFS) compared to standard treatment. As such, CAR T-cell therapy represents the new standard of care for second-line treatment in appropriate patients with refractory or early relapsing LBCL.

There have been several other recent studies on the use of CAR T-cell therapy for B-cell lymphoma. One study, published in Blood Advances (2023), found that receiving a greater number of therapies prior to CAR T-cell therapy is associated with poorer outcomes in patients with aggressive relapsed/refractory B-cell NHL. The study, which included 514 patients from 13 centers treated with CAR-T for aggressive B-cell NHL between 2015 and 2021, found that a greater number of lines of therapy before CAR-T apheresis and bridging therapy were predictive of inferior PFS and overall survival. 

Another study compared 2 CD19-targeting CAR T-cell treatments, axi-cel and tisa-cel, with ASCT in the second line setting for LBCL. The study found that axi-cel was superior to ASCT, with longer median event-free survival and a higher response rate. However, tisa-cel was not found to be superior to ASCT. Further studies will be needed to definitively characterize the relative benefits of CAR-T cell therapies and standard second-line treatments for different subgroups of patients with LBCL. 

An increasing number of effective targeted agents for DLBCL, including novel monoclonal antibodies (tafasitamab) and antibody-drug conjugates (polatuzumab vedotin and loncastuximab teserine), are being used in earlier lines of therapy. Additionally, 2 anti-CD20 bispecific antibodies (epcoritamab and glofitamab) have gained approval for relapsed/refractory DLBCL due to high response rates. Future studies will be needed to determine if treatment with these agents can produce durable remissions like that of CAR-T cell therapy.

Patients with chronic insomnia that does not improve with nonpharmacologic techniques often develop tolerance to sedative medications (benzodiazepines) prescribed for nightly use. When nonbenzodiazepine medications are used, tachyphylaxis can develop and these medications no longer initiate or maintain sleep. Strategies that alternate between these 2 types of agents are simple to follow and may allow patients to maintain sensitivity to both types of medications. In this article, I review the types, causes, evaluation, and treatment of insomnia; describe an alternating medication strategy to help patients avoid developing tolerance/tachyphylaxis; and present 3 fictional case vignettes to illustrate this approach.

A common, troubling condition

Insomnia is a common problem among psychiatric patients. Approximately 30% to 50% of adults experience occasional, short-term (<3 months) insomnia, and 5% to 10% experience chronic (≥3 months) insomnia,¹ with associated negative impacts on health and quality of life. Insomnia is sometimes primary and may have a hereditary component, but more often is associated with medical, neurologic, or psychiatric disorders.

Patterns of insomnia include difficulty falling asleep (initial or sleep-onset insomnia), remaining asleep (middle or sleep-maintenance insomnia), or falling back asleep after early awakening (late or sleep-offset insomnia). Sleep-onset insomnia correlates with high levels of anxiety and worrying, but once asleep, patients usually stay asleep. Sleep-maintenance problems involve multiple awakenings after falling asleep and taking hours to fall back to sleep. These patients experience inadequate sleep when they must wake up early for school or work. Early-awakening patients report feeling wide awake by 4 to 5 am and being unable to get back to sleep.

Caffeine is an important consideration for patients with sleep difficulties. Its use is widespread in much of the world, whether ingested as coffee, tea, in soft drinks, or in “energy” drinks that may contain as much as 200 mg of caffeine (twice the amount in a typical cup of brewed coffee). Caffeine may also be ingested as an ingredient of medications for headache or migraine. While some individuals maintain that they can fall asleep easily after drinking caffeinated coffee, many may not recognize the amount of caffeine they consume and its negative impact on sleep.² Author Michael Pollan stopped use of all caffeine and reported on the surprising positive effect on his sleep.³

Patients with mood, anxiety, or psychotic disorders are likely to experience insomnia intermittently or chronically, and insomnia predisposes some individuals to develop mood and anxiety symptoms.⁴ Patients with insomnia often experience anxiety focused on a fear of not getting adequate sleep, which creates a vicious cycle in which hyperarousal associated with fear of not sleeping complicates other causes of insomnia. A patient’s chronotype (preference for the time of day in which they carry out activities vs sleeping) also may play a role in sleep difficulties (Box⁵).

Box

Certain medications may contribute to insomnia, particularly stimulants. It is important to understand and explain to patients the time frame during which immediate-release or extended-release (ER) stimulants are active, which varies in individuals depending on liver enzyme activity. Other commonly used psychotropic medications—including bupropion, modafinil, armodafinil, atomoxetine, amphetamine salts, and methylphenidate—may interfere with sleep if used later in the day.⁶

Patients typically do not mention their use of alcohol and/or marijuana unless asked. Those who are binge drinkers or alcohol-dependent may expect alcohol to help them fall asleep, but usually find their sleep is disrupted and difficult to maintain. Patients may use marijuana to help them sleep, particularly marijuana high in tetrahydrocannabinol (THC). While it may help with sleep initiation, THC can disrupt sleep maintenance. Cannabidiol does not have intrinsic sedating effects and may even interfere with sleep.^7,8

Continue to: Women may be more likely...

Women may be more likely than men to experience insomnia.⁹ The onset of menopause can bring hot flashes that interfere with sleep.

Women with a history of mood disorders are more likely to have a history of premenstrual dysphoric disorder, postpartum depression, and unusual responses to oral contraceptives.¹⁰ These women are more likely to report problems with mood, energy, and sleep at perimenopause. Treatment with estrogen replacement may be an option for women without risk factors, such as clotting disorders, smoking history, or a personal or family history of breast or uterine cancer. For many who are not candidates for or who refuse estrogen replacement, use of a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor at low doses may help with vasomotor symptoms but not with insomnia.

Insomnia symptoms typically increase with age.¹¹ When sleep is adequate early in life but becomes a problem in midlife, an individual’s eating habits, obesity, and lack of exercise may be contributing factors. The typical American diet includes highly refined carbohydrates with excess salt; such foods are often readily available to the exclusion of healthy options. Overweight and obese patients may insist they eat a healthy diet with 3 meals per day, but a careful history often uncovers nighttime binge eating. Nighttime binge eating is rarely reported. This not only maintains obesity, but also interferes with sleep, since patients stay up late to avoid discovery by family members.¹² This lack of sleep can lead to an endless loop because insufficient sleep is a risk factor for obesity.¹³

Evaluating sleep difficulties

New patient evaluations should include a careful history beginning with childhood, including personal early childhood history and family psychiatric history. Patients often report the onset of sleep difficulty and anxiety during childhood, which should raise further questions about aspects of mood regulation from early life such as concentration, energy, motivation, appetite, and academic performance. While many children and adolescents are diagnosed with attention-deficit/hyperactivity disorder due to concentration problems that cause difficulties at school, be aware this might be part of a syndrome related to mood regulation.¹⁴ Unexpected responses to an SSRI—such as agitation, euphoria, or an immediate response with the first dose—should also raise suspicion of a mood disorder. Once the underlying mood disorder is stabilized, many patients report improved sleep.¹⁵

If a patient reports having difficulty falling and remaining asleep but is not sure if there is a pattern, keeping a sleep diary can help. Further questioning may uncover the cause. Does the patient have spontaneous jerks of lower extremities (restless leg syndrome) that interfere with falling asleep or wake them up? Have they noticed problems with dreams/nightmares that wake them, which could be associated with posttraumatic stress, anxiety, or depression? Have they been told by a partner that they act out dreams or are seemingly awake but not responsive, which could point to REM sleep behavior disorder or early Parkinson’s disease? Referral to a sleep laboratory and a neurologist can help establish the correct diagnosis and point to appropriate treatment.^16-18

Treatment options

Several cognitive-behavioral techniques, including cognitive-behavioral therapy for insomnia (CBT-I), yogic breathing, progressive relaxation, mindfulness meditation, and sleep hygiene techniques may help considerably,^19,20 but insomnia often remains difficult to treat. Pharmacotherapy is not necessarily more effective than nonpharmacologic approaches. Both options require the patient to take initiative to either find nonpharmacologic approaches or discuss the problem with a physician and agree to take medication.²¹ A trial comparing CBT-I to sedatives or the combination of CBT-I plus sedatives found higher rates of sleep with CBT-I for 3 months, after which improvement fluctuated; the combination showed sustained improvement for the entire 6-month trial.²² CBT-I has also been shown to be as effective with patients who do not have psychiatric illness as for those who are depressed, anxious, or stressed.²³ However, behavioral techniques that require regular practice may be difficult for individuals to maintain, particularly when they are depressed or anxious.

Continue to: Clinicians should understand...

Clinicians should understand the distinctions among the various types of pharmacotherapy for insomnia. Sedative-hypnotics include medications with varying half-lives and metabolic pathways. Short-acting benzodiazepines such as triazolam or alprazolam and the “z-drugs” zolpidem or zaleplon may help initiate sleep in patients with sleep-onset insomnia. Longer-acting benzodiazepines such as diazepam, clonazepam, or temazepam and the z-drug eszopiclone may also help with sleep maintenance.²³ Based on my clinical experience, individual patients may respond better to 1 type of medication over another, or even to different agents within the same class of sedative-hypnotics.

Some clinicians prescribe nonbenzodiazepine medications for sleep, such as doxepin (which is FDA-approved for treating insomnia) or off-label trazodone, mirtazapine, or quetiapine. Their antihistaminic properties confer sedating effects. Virtually all over-the-counter (OTC) medications for insomnia are antihistaminic. These OTC medications are not designed to treat insomnia, and the optimal dosage to maintain sleep without daytime sedation must be determined by trial and error. Sedating nonbenzodiazepine medications may be slowly absorbed if taken at bedtime (depending on whether they are taken with or without food) and cause daytime sedation and cognitive slowness in patients with sleep-onset and maintenance insomnia who must wake up early. Starting trazodone at 50 to 75 mg may cause slow metabolizers to wake up with considerable sedation, while fast metabolizers might never feel soundly asleep.²⁴

Patients with mood and anxiety disorders that complicate insomnia are often prescribed second-generation antipsychotics such as quetiapine, lurasidone, or olanzapine, which are sedating as well as mood-stabilizing. These approaches require careful attention to titrating doses and timing their use.

Problems with pharmacotherapy

When either benzodiazepines or nonbenzodiazepine medications are used on a long-standing, nightly basis, they often stop working well. It is not unusual that after days to weeks of taking a benzodiazepine, patients find they no longer stay asleep but can’t fall asleep if they don’t take them. Once tolerance develops, the individual experiences pharmacologic withdrawal with an inability to fall asleep or stay asleep. The medication becomes necessary but ineffective, and many patients increase their use to higher doses to fall asleep, and sometimes in early morning to maintain sleep. This leads to negative effects on cognition, coordination/balance, and mood during the day, especially in older patients.

Nonbenzodiazepine sedating medications do not lead to pharmacologic tolerance but do lead to tachyphylaxis as the CNS attempts to downregulate sedation to keep the organism safe. For some patients, this happens quickly, within a matter of days.²⁵ Others increase doses to stay asleep. For example, a patient with a starting dose of trazodone 75 mg/d might increase the dosage to 300 mg/d. While trazodone is approved in doses of 300 to 600 mg as an antidepressant, it is preferable to keep doses lower when used only for sedation.

Continue to: An alternating medication strategy

Alternating between medications from different classes can help patients avoid developing tolerance with benzodiazepines or tachyphylaxis as occurs with antihistaminic medications. It can be effective for patients with primary insomnia as well as for those whose sleep problems are associated with mood or anxiety disorders. Patients typically maintain sensitivity to any form of pharmacologic sedation for several nights without loss of effect but need to take a break to maintain the sedation effect. For example, in 1 case study, a 30-year-old female who rapidly developed tachyphylaxis to the sedative action of mirtazapine experienced a return of the medication’s sedative effects after taking a 3-day break.²⁵

To initiate an alternating strategy, the clinician must first help the patient establish a sedating dose of 2 medications from different classes, such as trazodone and zolpidem, and then instruct the patient to use each for 2 to 3 consecutive nights on an alternating basis. Patients can use calendars or pillboxes to avoid confusion about which medication to take on a given night. In many cases, this approach can work indefinitely.

The following 3 case vignettes illustrate how this alternating medication strategy can work.

CASE 1

Mr. B, age 58, is a married salesman whose territory includes 3 states. He drives from client to client from Monday through Thursday each week, staying overnight in hotels. He is comfortable talking to clients, has a close and supportive relationship with his wife, and enjoys socializing with friends. Mr. B has a high level of trait anxiety and perfectionism and is proud of his sales record throughout his career, but this leads to insomnia during his nights on the road, and often on Sunday night as he starts anticipating the week ahead. Mr. B denies having a depressed mood or cognitive problems. When on vacation with his wife he has no trouble sleeping. He has no psychiatric family history or any substantial medical problems. He simply wishes that he could sleep on work nights.

We set up an alternating medication approach. Mr. B takes trazodone 100 mg on the first night and 150 mg on the second and third nights. He then takes triazolam 0.25 mg for 2 nights; previously, he had found that zolpidem did not work as well for maintaining sleep. He can sleep adequately for the 2 weekend nights, then restarts the alternating pattern. Mr. B has done well with this regimen for >10 years.

Continue to: CASE 2

Ms. C, age 60, is widowed and has a successful career as a corporate attorney. She has been anxious since early childhood and has had trouble falling asleep for much of her life. Once she falls asleep on her sofa—often between 1 and 2 am—Ms. C can sleep soundly for 7 to 8 hours, but early morning work meetings require her to set an alarm for 6 am daily. Ms. C feels irritable and anxious on awakening but arrives at her office by 7:30 am, where she maintains a full schedule, with frequent 12-hour workdays. Ms. C did not experience significant insomnia or hot flashes with menopause at age 52 and does not use hormone replacement therapy.

Ms. C denies having depression, but experienced appropriate grief related to her husband’s illness and death from metastatic cancer 3 years ago. At the time, her internist prescribed escitalopram and zolpidem; escitalopram caused greater agitation and distress, so she stopped it after 10 days. Zolpidem 10 mg/d allowed her to sleep but she worried about taking it because her mother had long-standing sedative dependence. Ms. C lives alone, but her adult children live nearby, and she has a strong support system that includes colleagues at her firm, friends at her book club, and a support group for partners of cancer patients.

Ms. C tries trazodone, starting with 50 mg, but reports feeling agitated rather than sleepy and has cognitive fogginess in the morning. She is switched to quetiapine 50 mg, which she tolerates well and allows her to sleep soundly. To avoid developing tachyphylaxis with quetiapine, she takes eszopiclone 3 mg for 2 nights, alternating with quetiapine for 3 nights. This strategy allows her to reliably fall asleep by 11 pm, wake up at 6 am, and feel rested throughout the day.

CASE 3

Ms. D, age 55, is married with a long-standing diagnosis of generalized anxiety disorder (GAD), panic disorder, and depression so severe she is unable to work as a preschool teacher. She notes that past clinicians have prescribed a wide array of antidepressants and benzodiazepines but she remains anxious, agitated, and unable to sleep. She worries constantly about running out of benzodiazepines, which are “the only medication that helps me.” At the time of evaluation, her medications are venlafaxine ER 150 mg/d, lorazepam 1 mg 3 times daily and 2 mg at bedtime, and buspirone 15 mg 3 times daily, which she admits to not taking. She is overweight and does not exercise. She spends her days snacking and watching television. She can’t settle down enough to read and feels overwhelmed most of the time. Her adult children won’t allow her to babysit their young children because she dozes during the day.

Ms. D has a strong family history of psychiatric illness, including a father with bipolar I disorder and alcohol use disorder and a sister with schizoaffective disorder. Ms. D has never felt overtly manic, but has spent most of her life feeling depressed, anxious, and hopeless, and at times she has wished she was dead. She has had poor responses to many antidepressants, with transient euphoria followed by more anxiety.

Continue to: Rather than major depressive disorder...

Rather than major depressive disorder or GAD, Ms. D’s symptoms better meet the criteria for bipolar II disorder. She agrees to a slow taper of venlafaxine and a slow increase of divalproex, starting with 125 mg each evening. While taking venlafaxine 75 mg/d and divalproex 375 mg/d, she experiences distinct improvement in anxiety and agitation, which further improve after venlafaxine is stopped and divalproex is increased to 750 mg in the evening. She finds that she forgets daytime doses of lorazepam but depends on it to fall asleep. While taking quetiapine 50 mg and lorazepam 1 mg at bedtime, Ms. D reports sleeping soundly and feeling alert in the morning. Over several weeks, she tapers lorazepam slowly by 0.5 mg every 2 weeks. She finds she needs a higher dose of quetiapine to stay asleep, eventually requiring 400 mg each night. Ms. D says overall she feels better but is distressed because she has gained 25 lbs since starting divalproex and quetiapine.

To avoid further increases in quetiapine and maintain its sedating effect, Ms. D is switched to an alternating schedule of clonazepam 1.5 mg for 2 nights and quetiapine 300 mg for 3 nights. She agrees to begin exercising by walking in her neighborhood daily, and gradually increases this to 1 hour per day. After starting to exercise regularly, she finds she is oversedated by quetiapine at night, so she is gradually decreased to a dose of 150 mg, while still alternating with clonazepam 1.5 mg. Ms. D loses most of the weight she had gained and begins volunteering as a reading coach in the elementary school in her neighborhood.

Bottom Line

Patients with chronic insomnia can often maintain adequate sedation without developing tolerance to benzodiazepines or tachyphylaxis with nonsedating agents by using 2 sleep medications that have different mechanisms of action on an alternating schedule.

Related Resources

• Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2): 307-349. doi:10.5664/jcsm.6470
• Muppavarapu K, Muthukanagaraj M, Saeed SA. Cognitive-behavioral therapy for insomnia: a review of 8 studies. Current Psychiatry. 2020;19(9):40-46. doi:10.12788/cp.0040

Drug Brand Names

Alprazolam • Xanax
Armodafinil • Nuvigil
Atomoxetine • Strattera
Bupropion • Wellbutrin
Clonazepam • Klonopin
Diazepam • Valium
Divalproex • Depakote
Doxepin • Sinequan
Escitalopram • Lexapro
Eszopiclone • Lunesta
Lorazepam • Ativan
Lurasidone • Latuda
Methylphenidate • Concerta
Mirtazapine • Remeron
Modafinil • Provigil
Olanzapine • Zyprexa
Quetiapine • Seroquel
Temazepam • Restoril
Trazodone • Desyrel
Triazolam • Halcion
Venlafaxine • Effexor
Zaleplon • Sonata
Zolpidem • Ambien

Patients with chronic insomnia that does not improve with nonpharmacologic techniques often develop tolerance to sedative medications (benzodiazepines) prescribed for nightly use. When nonbenzodiazepine medications are used, tachyphylaxis can develop and these medications no longer initiate or maintain sleep. Strategies that alternate between these 2 types of agents are simple to follow and may allow patients to maintain sensitivity to both types of medications. In this article, I review the types, causes, evaluation, and treatment of insomnia; describe an alternating medication strategy to help patients avoid developing tolerance/tachyphylaxis; and present 3 fictional case vignettes to illustrate this approach.

A common, troubling condition

Insomnia is a common problem among psychiatric patients. Approximately 30% to 50% of adults experience occasional, short-term (<3 months) insomnia, and 5% to 10% experience chronic (≥3 months) insomnia,¹ with associated negative impacts on health and quality of life. Insomnia is sometimes primary and may have a hereditary component, but more often is associated with medical, neurologic, or psychiatric disorders.

Patterns of insomnia include difficulty falling asleep (initial or sleep-onset insomnia), remaining asleep (middle or sleep-maintenance insomnia), or falling back asleep after early awakening (late or sleep-offset insomnia). Sleep-onset insomnia correlates with high levels of anxiety and worrying, but once asleep, patients usually stay asleep. Sleep-maintenance problems involve multiple awakenings after falling asleep and taking hours to fall back to sleep. These patients experience inadequate sleep when they must wake up early for school or work. Early-awakening patients report feeling wide awake by 4 to 5 am and being unable to get back to sleep.

Caffeine is an important consideration for patients with sleep difficulties. Its use is widespread in much of the world, whether ingested as coffee, tea, in soft drinks, or in “energy” drinks that may contain as much as 200 mg of caffeine (twice the amount in a typical cup of brewed coffee). Caffeine may also be ingested as an ingredient of medications for headache or migraine. While some individuals maintain that they can fall asleep easily after drinking caffeinated coffee, many may not recognize the amount of caffeine they consume and its negative impact on sleep.² Author Michael Pollan stopped use of all caffeine and reported on the surprising positive effect on his sleep.³

Patients with mood, anxiety, or psychotic disorders are likely to experience insomnia intermittently or chronically, and insomnia predisposes some individuals to develop mood and anxiety symptoms.⁴ Patients with insomnia often experience anxiety focused on a fear of not getting adequate sleep, which creates a vicious cycle in which hyperarousal associated with fear of not sleeping complicates other causes of insomnia. A patient’s chronotype (preference for the time of day in which they carry out activities vs sleeping) also may play a role in sleep difficulties (Box⁵).

Box

Certain medications may contribute to insomnia, particularly stimulants. It is important to understand and explain to patients the time frame during which immediate-release or extended-release (ER) stimulants are active, which varies in individuals depending on liver enzyme activity. Other commonly used psychotropic medications—including bupropion, modafinil, armodafinil, atomoxetine, amphetamine salts, and methylphenidate—may interfere with sleep if used later in the day.⁶

Patients typically do not mention their use of alcohol and/or marijuana unless asked. Those who are binge drinkers or alcohol-dependent may expect alcohol to help them fall asleep, but usually find their sleep is disrupted and difficult to maintain. Patients may use marijuana to help them sleep, particularly marijuana high in tetrahydrocannabinol (THC). While it may help with sleep initiation, THC can disrupt sleep maintenance. Cannabidiol does not have intrinsic sedating effects and may even interfere with sleep.^7,8

Continue to: Women may be more likely...

Women may be more likely than men to experience insomnia.⁹ The onset of menopause can bring hot flashes that interfere with sleep.

Women with a history of mood disorders are more likely to have a history of premenstrual dysphoric disorder, postpartum depression, and unusual responses to oral contraceptives.¹⁰ These women are more likely to report problems with mood, energy, and sleep at perimenopause. Treatment with estrogen replacement may be an option for women without risk factors, such as clotting disorders, smoking history, or a personal or family history of breast or uterine cancer. For many who are not candidates for or who refuse estrogen replacement, use of a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor at low doses may help with vasomotor symptoms but not with insomnia.

Insomnia symptoms typically increase with age.¹¹ When sleep is adequate early in life but becomes a problem in midlife, an individual’s eating habits, obesity, and lack of exercise may be contributing factors. The typical American diet includes highly refined carbohydrates with excess salt; such foods are often readily available to the exclusion of healthy options. Overweight and obese patients may insist they eat a healthy diet with 3 meals per day, but a careful history often uncovers nighttime binge eating. Nighttime binge eating is rarely reported. This not only maintains obesity, but also interferes with sleep, since patients stay up late to avoid discovery by family members.¹² This lack of sleep can lead to an endless loop because insufficient sleep is a risk factor for obesity.¹³

Evaluating sleep difficulties

New patient evaluations should include a careful history beginning with childhood, including personal early childhood history and family psychiatric history. Patients often report the onset of sleep difficulty and anxiety during childhood, which should raise further questions about aspects of mood regulation from early life such as concentration, energy, motivation, appetite, and academic performance. While many children and adolescents are diagnosed with attention-deficit/hyperactivity disorder due to concentration problems that cause difficulties at school, be aware this might be part of a syndrome related to mood regulation.¹⁴ Unexpected responses to an SSRI—such as agitation, euphoria, or an immediate response with the first dose—should also raise suspicion of a mood disorder. Once the underlying mood disorder is stabilized, many patients report improved sleep.¹⁵

If a patient reports having difficulty falling and remaining asleep but is not sure if there is a pattern, keeping a sleep diary can help. Further questioning may uncover the cause. Does the patient have spontaneous jerks of lower extremities (restless leg syndrome) that interfere with falling asleep or wake them up? Have they noticed problems with dreams/nightmares that wake them, which could be associated with posttraumatic stress, anxiety, or depression? Have they been told by a partner that they act out dreams or are seemingly awake but not responsive, which could point to REM sleep behavior disorder or early Parkinson’s disease? Referral to a sleep laboratory and a neurologist can help establish the correct diagnosis and point to appropriate treatment.^16-18

Treatment options

Several cognitive-behavioral techniques, including cognitive-behavioral therapy for insomnia (CBT-I), yogic breathing, progressive relaxation, mindfulness meditation, and sleep hygiene techniques may help considerably,^19,20 but insomnia often remains difficult to treat. Pharmacotherapy is not necessarily more effective than nonpharmacologic approaches. Both options require the patient to take initiative to either find nonpharmacologic approaches or discuss the problem with a physician and agree to take medication.²¹ A trial comparing CBT-I to sedatives or the combination of CBT-I plus sedatives found higher rates of sleep with CBT-I for 3 months, after which improvement fluctuated; the combination showed sustained improvement for the entire 6-month trial.²² CBT-I has also been shown to be as effective with patients who do not have psychiatric illness as for those who are depressed, anxious, or stressed.²³ However, behavioral techniques that require regular practice may be difficult for individuals to maintain, particularly when they are depressed or anxious.

Continue to: Clinicians should understand...

Clinicians should understand the distinctions among the various types of pharmacotherapy for insomnia. Sedative-hypnotics include medications with varying half-lives and metabolic pathways. Short-acting benzodiazepines such as triazolam or alprazolam and the “z-drugs” zolpidem or zaleplon may help initiate sleep in patients with sleep-onset insomnia. Longer-acting benzodiazepines such as diazepam, clonazepam, or temazepam and the z-drug eszopiclone may also help with sleep maintenance.²³ Based on my clinical experience, individual patients may respond better to 1 type of medication over another, or even to different agents within the same class of sedative-hypnotics.

Some clinicians prescribe nonbenzodiazepine medications for sleep, such as doxepin (which is FDA-approved for treating insomnia) or off-label trazodone, mirtazapine, or quetiapine. Their antihistaminic properties confer sedating effects. Virtually all over-the-counter (OTC) medications for insomnia are antihistaminic. These OTC medications are not designed to treat insomnia, and the optimal dosage to maintain sleep without daytime sedation must be determined by trial and error. Sedating nonbenzodiazepine medications may be slowly absorbed if taken at bedtime (depending on whether they are taken with or without food) and cause daytime sedation and cognitive slowness in patients with sleep-onset and maintenance insomnia who must wake up early. Starting trazodone at 50 to 75 mg may cause slow metabolizers to wake up with considerable sedation, while fast metabolizers might never feel soundly asleep.²⁴

Patients with mood and anxiety disorders that complicate insomnia are often prescribed second-generation antipsychotics such as quetiapine, lurasidone, or olanzapine, which are sedating as well as mood-stabilizing. These approaches require careful attention to titrating doses and timing their use.

Problems with pharmacotherapy

When either benzodiazepines or nonbenzodiazepine medications are used on a long-standing, nightly basis, they often stop working well. It is not unusual that after days to weeks of taking a benzodiazepine, patients find they no longer stay asleep but can’t fall asleep if they don’t take them. Once tolerance develops, the individual experiences pharmacologic withdrawal with an inability to fall asleep or stay asleep. The medication becomes necessary but ineffective, and many patients increase their use to higher doses to fall asleep, and sometimes in early morning to maintain sleep. This leads to negative effects on cognition, coordination/balance, and mood during the day, especially in older patients.

Nonbenzodiazepine sedating medications do not lead to pharmacologic tolerance but do lead to tachyphylaxis as the CNS attempts to downregulate sedation to keep the organism safe. For some patients, this happens quickly, within a matter of days.²⁵ Others increase doses to stay asleep. For example, a patient with a starting dose of trazodone 75 mg/d might increase the dosage to 300 mg/d. While trazodone is approved in doses of 300 to 600 mg as an antidepressant, it is preferable to keep doses lower when used only for sedation.

Continue to: An alternating medication strategy

Alternating between medications from different classes can help patients avoid developing tolerance with benzodiazepines or tachyphylaxis as occurs with antihistaminic medications. It can be effective for patients with primary insomnia as well as for those whose sleep problems are associated with mood or anxiety disorders. Patients typically maintain sensitivity to any form of pharmacologic sedation for several nights without loss of effect but need to take a break to maintain the sedation effect. For example, in 1 case study, a 30-year-old female who rapidly developed tachyphylaxis to the sedative action of mirtazapine experienced a return of the medication’s sedative effects after taking a 3-day break.²⁵

To initiate an alternating strategy, the clinician must first help the patient establish a sedating dose of 2 medications from different classes, such as trazodone and zolpidem, and then instruct the patient to use each for 2 to 3 consecutive nights on an alternating basis. Patients can use calendars or pillboxes to avoid confusion about which medication to take on a given night. In many cases, this approach can work indefinitely.

The following 3 case vignettes illustrate how this alternating medication strategy can work.

CASE 1

Mr. B, age 58, is a married salesman whose territory includes 3 states. He drives from client to client from Monday through Thursday each week, staying overnight in hotels. He is comfortable talking to clients, has a close and supportive relationship with his wife, and enjoys socializing with friends. Mr. B has a high level of trait anxiety and perfectionism and is proud of his sales record throughout his career, but this leads to insomnia during his nights on the road, and often on Sunday night as he starts anticipating the week ahead. Mr. B denies having a depressed mood or cognitive problems. When on vacation with his wife he has no trouble sleeping. He has no psychiatric family history or any substantial medical problems. He simply wishes that he could sleep on work nights.

We set up an alternating medication approach. Mr. B takes trazodone 100 mg on the first night and 150 mg on the second and third nights. He then takes triazolam 0.25 mg for 2 nights; previously, he had found that zolpidem did not work as well for maintaining sleep. He can sleep adequately for the 2 weekend nights, then restarts the alternating pattern. Mr. B has done well with this regimen for >10 years.

Continue to: CASE 2

Ms. C, age 60, is widowed and has a successful career as a corporate attorney. She has been anxious since early childhood and has had trouble falling asleep for much of her life. Once she falls asleep on her sofa—often between 1 and 2 am—Ms. C can sleep soundly for 7 to 8 hours, but early morning work meetings require her to set an alarm for 6 am daily. Ms. C feels irritable and anxious on awakening but arrives at her office by 7:30 am, where she maintains a full schedule, with frequent 12-hour workdays. Ms. C did not experience significant insomnia or hot flashes with menopause at age 52 and does not use hormone replacement therapy.

Ms. C denies having depression, but experienced appropriate grief related to her husband’s illness and death from metastatic cancer 3 years ago. At the time, her internist prescribed escitalopram and zolpidem; escitalopram caused greater agitation and distress, so she stopped it after 10 days. Zolpidem 10 mg/d allowed her to sleep but she worried about taking it because her mother had long-standing sedative dependence. Ms. C lives alone, but her adult children live nearby, and she has a strong support system that includes colleagues at her firm, friends at her book club, and a support group for partners of cancer patients.

Ms. C tries trazodone, starting with 50 mg, but reports feeling agitated rather than sleepy and has cognitive fogginess in the morning. She is switched to quetiapine 50 mg, which she tolerates well and allows her to sleep soundly. To avoid developing tachyphylaxis with quetiapine, she takes eszopiclone 3 mg for 2 nights, alternating with quetiapine for 3 nights. This strategy allows her to reliably fall asleep by 11 pm, wake up at 6 am, and feel rested throughout the day.

CASE 3

Ms. D, age 55, is married with a long-standing diagnosis of generalized anxiety disorder (GAD), panic disorder, and depression so severe she is unable to work as a preschool teacher. She notes that past clinicians have prescribed a wide array of antidepressants and benzodiazepines but she remains anxious, agitated, and unable to sleep. She worries constantly about running out of benzodiazepines, which are “the only medication that helps me.” At the time of evaluation, her medications are venlafaxine ER 150 mg/d, lorazepam 1 mg 3 times daily and 2 mg at bedtime, and buspirone 15 mg 3 times daily, which she admits to not taking. She is overweight and does not exercise. She spends her days snacking and watching television. She can’t settle down enough to read and feels overwhelmed most of the time. Her adult children won’t allow her to babysit their young children because she dozes during the day.

Ms. D has a strong family history of psychiatric illness, including a father with bipolar I disorder and alcohol use disorder and a sister with schizoaffective disorder. Ms. D has never felt overtly manic, but has spent most of her life feeling depressed, anxious, and hopeless, and at times she has wished she was dead. She has had poor responses to many antidepressants, with transient euphoria followed by more anxiety.

Continue to: Rather than major depressive disorder...

Rather than major depressive disorder or GAD, Ms. D’s symptoms better meet the criteria for bipolar II disorder. She agrees to a slow taper of venlafaxine and a slow increase of divalproex, starting with 125 mg each evening. While taking venlafaxine 75 mg/d and divalproex 375 mg/d, she experiences distinct improvement in anxiety and agitation, which further improve after venlafaxine is stopped and divalproex is increased to 750 mg in the evening. She finds that she forgets daytime doses of lorazepam but depends on it to fall asleep. While taking quetiapine 50 mg and lorazepam 1 mg at bedtime, Ms. D reports sleeping soundly and feeling alert in the morning. Over several weeks, she tapers lorazepam slowly by 0.5 mg every 2 weeks. She finds she needs a higher dose of quetiapine to stay asleep, eventually requiring 400 mg each night. Ms. D says overall she feels better but is distressed because she has gained 25 lbs since starting divalproex and quetiapine.

To avoid further increases in quetiapine and maintain its sedating effect, Ms. D is switched to an alternating schedule of clonazepam 1.5 mg for 2 nights and quetiapine 300 mg for 3 nights. She agrees to begin exercising by walking in her neighborhood daily, and gradually increases this to 1 hour per day. After starting to exercise regularly, she finds she is oversedated by quetiapine at night, so she is gradually decreased to a dose of 150 mg, while still alternating with clonazepam 1.5 mg. Ms. D loses most of the weight she had gained and begins volunteering as a reading coach in the elementary school in her neighborhood.

Bottom Line

Patients with chronic insomnia can often maintain adequate sedation without developing tolerance to benzodiazepines or tachyphylaxis with nonsedating agents by using 2 sleep medications that have different mechanisms of action on an alternating schedule.

Related Resources

• Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2): 307-349. doi:10.5664/jcsm.6470
• Muppavarapu K, Muthukanagaraj M, Saeed SA. Cognitive-behavioral therapy for insomnia: a review of 8 studies. Current Psychiatry. 2020;19(9):40-46. doi:10.12788/cp.0040

Drug Brand Names

Alprazolam • Xanax
Armodafinil • Nuvigil
Atomoxetine • Strattera
Bupropion • Wellbutrin
Clonazepam • Klonopin
Diazepam • Valium
Divalproex • Depakote
Doxepin • Sinequan
Escitalopram • Lexapro
Eszopiclone • Lunesta
Lorazepam • Ativan
Lurasidone • Latuda
Methylphenidate • Concerta
Mirtazapine • Remeron
Modafinil • Provigil
Olanzapine • Zyprexa
Quetiapine • Seroquel
Temazepam • Restoril
Trazodone • Desyrel
Triazolam • Halcion
Venlafaxine • Effexor
Zaleplon • Sonata
Zolpidem • Ambien

Patients with chronic insomnia that does not improve with nonpharmacologic techniques often develop tolerance to sedative medications (benzodiazepines) prescribed for nightly use. When nonbenzodiazepine medications are used, tachyphylaxis can develop and these medications no longer initiate or maintain sleep. Strategies that alternate between these 2 types of agents are simple to follow and may allow patients to maintain sensitivity to both types of medications. In this article, I review the types, causes, evaluation, and treatment of insomnia; describe an alternating medication strategy to help patients avoid developing tolerance/tachyphylaxis; and present 3 fictional case vignettes to illustrate this approach.

A common, troubling condition

Insomnia is a common problem among psychiatric patients. Approximately 30% to 50% of adults experience occasional, short-term (<3 months) insomnia, and 5% to 10% experience chronic (≥3 months) insomnia,¹ with associated negative impacts on health and quality of life. Insomnia is sometimes primary and may have a hereditary component, but more often is associated with medical, neurologic, or psychiatric disorders.

Patterns of insomnia include difficulty falling asleep (initial or sleep-onset insomnia), remaining asleep (middle or sleep-maintenance insomnia), or falling back asleep after early awakening (late or sleep-offset insomnia). Sleep-onset insomnia correlates with high levels of anxiety and worrying, but once asleep, patients usually stay asleep. Sleep-maintenance problems involve multiple awakenings after falling asleep and taking hours to fall back to sleep. These patients experience inadequate sleep when they must wake up early for school or work. Early-awakening patients report feeling wide awake by 4 to 5 am and being unable to get back to sleep.

Caffeine is an important consideration for patients with sleep difficulties. Its use is widespread in much of the world, whether ingested as coffee, tea, in soft drinks, or in “energy” drinks that may contain as much as 200 mg of caffeine (twice the amount in a typical cup of brewed coffee). Caffeine may also be ingested as an ingredient of medications for headache or migraine. While some individuals maintain that they can fall asleep easily after drinking caffeinated coffee, many may not recognize the amount of caffeine they consume and its negative impact on sleep.² Author Michael Pollan stopped use of all caffeine and reported on the surprising positive effect on his sleep.³

Patients with mood, anxiety, or psychotic disorders are likely to experience insomnia intermittently or chronically, and insomnia predisposes some individuals to develop mood and anxiety symptoms.⁴ Patients with insomnia often experience anxiety focused on a fear of not getting adequate sleep, which creates a vicious cycle in which hyperarousal associated with fear of not sleeping complicates other causes of insomnia. A patient’s chronotype (preference for the time of day in which they carry out activities vs sleeping) also may play a role in sleep difficulties (Box⁵).

Box

Certain medications may contribute to insomnia, particularly stimulants. It is important to understand and explain to patients the time frame during which immediate-release or extended-release (ER) stimulants are active, which varies in individuals depending on liver enzyme activity. Other commonly used psychotropic medications—including bupropion, modafinil, armodafinil, atomoxetine, amphetamine salts, and methylphenidate—may interfere with sleep if used later in the day.⁶

Patients typically do not mention their use of alcohol and/or marijuana unless asked. Those who are binge drinkers or alcohol-dependent may expect alcohol to help them fall asleep, but usually find their sleep is disrupted and difficult to maintain. Patients may use marijuana to help them sleep, particularly marijuana high in tetrahydrocannabinol (THC). While it may help with sleep initiation, THC can disrupt sleep maintenance. Cannabidiol does not have intrinsic sedating effects and may even interfere with sleep.^7,8

Continue to: Women may be more likely...

Women may be more likely than men to experience insomnia.⁹ The onset of menopause can bring hot flashes that interfere with sleep.

Women with a history of mood disorders are more likely to have a history of premenstrual dysphoric disorder, postpartum depression, and unusual responses to oral contraceptives.¹⁰ These women are more likely to report problems with mood, energy, and sleep at perimenopause. Treatment with estrogen replacement may be an option for women without risk factors, such as clotting disorders, smoking history, or a personal or family history of breast or uterine cancer. For many who are not candidates for or who refuse estrogen replacement, use of a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor at low doses may help with vasomotor symptoms but not with insomnia.

Insomnia symptoms typically increase with age.¹¹ When sleep is adequate early in life but becomes a problem in midlife, an individual’s eating habits, obesity, and lack of exercise may be contributing factors. The typical American diet includes highly refined carbohydrates with excess salt; such foods are often readily available to the exclusion of healthy options. Overweight and obese patients may insist they eat a healthy diet with 3 meals per day, but a careful history often uncovers nighttime binge eating. Nighttime binge eating is rarely reported. This not only maintains obesity, but also interferes with sleep, since patients stay up late to avoid discovery by family members.¹² This lack of sleep can lead to an endless loop because insufficient sleep is a risk factor for obesity.¹³

Evaluating sleep difficulties

New patient evaluations should include a careful history beginning with childhood, including personal early childhood history and family psychiatric history. Patients often report the onset of sleep difficulty and anxiety during childhood, which should raise further questions about aspects of mood regulation from early life such as concentration, energy, motivation, appetite, and academic performance. While many children and adolescents are diagnosed with attention-deficit/hyperactivity disorder due to concentration problems that cause difficulties at school, be aware this might be part of a syndrome related to mood regulation.¹⁴ Unexpected responses to an SSRI—such as agitation, euphoria, or an immediate response with the first dose—should also raise suspicion of a mood disorder. Once the underlying mood disorder is stabilized, many patients report improved sleep.¹⁵

If a patient reports having difficulty falling and remaining asleep but is not sure if there is a pattern, keeping a sleep diary can help. Further questioning may uncover the cause. Does the patient have spontaneous jerks of lower extremities (restless leg syndrome) that interfere with falling asleep or wake them up? Have they noticed problems with dreams/nightmares that wake them, which could be associated with posttraumatic stress, anxiety, or depression? Have they been told by a partner that they act out dreams or are seemingly awake but not responsive, which could point to REM sleep behavior disorder or early Parkinson’s disease? Referral to a sleep laboratory and a neurologist can help establish the correct diagnosis and point to appropriate treatment.^16-18

Treatment options

Several cognitive-behavioral techniques, including cognitive-behavioral therapy for insomnia (CBT-I), yogic breathing, progressive relaxation, mindfulness meditation, and sleep hygiene techniques may help considerably,^19,20 but insomnia often remains difficult to treat. Pharmacotherapy is not necessarily more effective than nonpharmacologic approaches. Both options require the patient to take initiative to either find nonpharmacologic approaches or discuss the problem with a physician and agree to take medication.²¹ A trial comparing CBT-I to sedatives or the combination of CBT-I plus sedatives found higher rates of sleep with CBT-I for 3 months, after which improvement fluctuated; the combination showed sustained improvement for the entire 6-month trial.²² CBT-I has also been shown to be as effective with patients who do not have psychiatric illness as for those who are depressed, anxious, or stressed.²³ However, behavioral techniques that require regular practice may be difficult for individuals to maintain, particularly when they are depressed or anxious.

Continue to: Clinicians should understand...

Clinicians should understand the distinctions among the various types of pharmacotherapy for insomnia. Sedative-hypnotics include medications with varying half-lives and metabolic pathways. Short-acting benzodiazepines such as triazolam or alprazolam and the “z-drugs” zolpidem or zaleplon may help initiate sleep in patients with sleep-onset insomnia. Longer-acting benzodiazepines such as diazepam, clonazepam, or temazepam and the z-drug eszopiclone may also help with sleep maintenance.²³ Based on my clinical experience, individual patients may respond better to 1 type of medication over another, or even to different agents within the same class of sedative-hypnotics.

Some clinicians prescribe nonbenzodiazepine medications for sleep, such as doxepin (which is FDA-approved for treating insomnia) or off-label trazodone, mirtazapine, or quetiapine. Their antihistaminic properties confer sedating effects. Virtually all over-the-counter (OTC) medications for insomnia are antihistaminic. These OTC medications are not designed to treat insomnia, and the optimal dosage to maintain sleep without daytime sedation must be determined by trial and error. Sedating nonbenzodiazepine medications may be slowly absorbed if taken at bedtime (depending on whether they are taken with or without food) and cause daytime sedation and cognitive slowness in patients with sleep-onset and maintenance insomnia who must wake up early. Starting trazodone at 50 to 75 mg may cause slow metabolizers to wake up with considerable sedation, while fast metabolizers might never feel soundly asleep.²⁴

Patients with mood and anxiety disorders that complicate insomnia are often prescribed second-generation antipsychotics such as quetiapine, lurasidone, or olanzapine, which are sedating as well as mood-stabilizing. These approaches require careful attention to titrating doses and timing their use.

Problems with pharmacotherapy

When either benzodiazepines or nonbenzodiazepine medications are used on a long-standing, nightly basis, they often stop working well. It is not unusual that after days to weeks of taking a benzodiazepine, patients find they no longer stay asleep but can’t fall asleep if they don’t take them. Once tolerance develops, the individual experiences pharmacologic withdrawal with an inability to fall asleep or stay asleep. The medication becomes necessary but ineffective, and many patients increase their use to higher doses to fall asleep, and sometimes in early morning to maintain sleep. This leads to negative effects on cognition, coordination/balance, and mood during the day, especially in older patients.

Nonbenzodiazepine sedating medications do not lead to pharmacologic tolerance but do lead to tachyphylaxis as the CNS attempts to downregulate sedation to keep the organism safe. For some patients, this happens quickly, within a matter of days.²⁵ Others increase doses to stay asleep. For example, a patient with a starting dose of trazodone 75 mg/d might increase the dosage to 300 mg/d. While trazodone is approved in doses of 300 to 600 mg as an antidepressant, it is preferable to keep doses lower when used only for sedation.

Continue to: An alternating medication strategy

Alternating between medications from different classes can help patients avoid developing tolerance with benzodiazepines or tachyphylaxis as occurs with antihistaminic medications. It can be effective for patients with primary insomnia as well as for those whose sleep problems are associated with mood or anxiety disorders. Patients typically maintain sensitivity to any form of pharmacologic sedation for several nights without loss of effect but need to take a break to maintain the sedation effect. For example, in 1 case study, a 30-year-old female who rapidly developed tachyphylaxis to the sedative action of mirtazapine experienced a return of the medication’s sedative effects after taking a 3-day break.²⁵

To initiate an alternating strategy, the clinician must first help the patient establish a sedating dose of 2 medications from different classes, such as trazodone and zolpidem, and then instruct the patient to use each for 2 to 3 consecutive nights on an alternating basis. Patients can use calendars or pillboxes to avoid confusion about which medication to take on a given night. In many cases, this approach can work indefinitely.

The following 3 case vignettes illustrate how this alternating medication strategy can work.

CASE 1

Mr. B, age 58, is a married salesman whose territory includes 3 states. He drives from client to client from Monday through Thursday each week, staying overnight in hotels. He is comfortable talking to clients, has a close and supportive relationship with his wife, and enjoys socializing with friends. Mr. B has a high level of trait anxiety and perfectionism and is proud of his sales record throughout his career, but this leads to insomnia during his nights on the road, and often on Sunday night as he starts anticipating the week ahead. Mr. B denies having a depressed mood or cognitive problems. When on vacation with his wife he has no trouble sleeping. He has no psychiatric family history or any substantial medical problems. He simply wishes that he could sleep on work nights.

We set up an alternating medication approach. Mr. B takes trazodone 100 mg on the first night and 150 mg on the second and third nights. He then takes triazolam 0.25 mg for 2 nights; previously, he had found that zolpidem did not work as well for maintaining sleep. He can sleep adequately for the 2 weekend nights, then restarts the alternating pattern. Mr. B has done well with this regimen for >10 years.

Continue to: CASE 2

Ms. C, age 60, is widowed and has a successful career as a corporate attorney. She has been anxious since early childhood and has had trouble falling asleep for much of her life. Once she falls asleep on her sofa—often between 1 and 2 am—Ms. C can sleep soundly for 7 to 8 hours, but early morning work meetings require her to set an alarm for 6 am daily. Ms. C feels irritable and anxious on awakening but arrives at her office by 7:30 am, where she maintains a full schedule, with frequent 12-hour workdays. Ms. C did not experience significant insomnia or hot flashes with menopause at age 52 and does not use hormone replacement therapy.

Ms. C denies having depression, but experienced appropriate grief related to her husband’s illness and death from metastatic cancer 3 years ago. At the time, her internist prescribed escitalopram and zolpidem; escitalopram caused greater agitation and distress, so she stopped it after 10 days. Zolpidem 10 mg/d allowed her to sleep but she worried about taking it because her mother had long-standing sedative dependence. Ms. C lives alone, but her adult children live nearby, and she has a strong support system that includes colleagues at her firm, friends at her book club, and a support group for partners of cancer patients.

Ms. C tries trazodone, starting with 50 mg, but reports feeling agitated rather than sleepy and has cognitive fogginess in the morning. She is switched to quetiapine 50 mg, which she tolerates well and allows her to sleep soundly. To avoid developing tachyphylaxis with quetiapine, she takes eszopiclone 3 mg for 2 nights, alternating with quetiapine for 3 nights. This strategy allows her to reliably fall asleep by 11 pm, wake up at 6 am, and feel rested throughout the day.

CASE 3

Ms. D, age 55, is married with a long-standing diagnosis of generalized anxiety disorder (GAD), panic disorder, and depression so severe she is unable to work as a preschool teacher. She notes that past clinicians have prescribed a wide array of antidepressants and benzodiazepines but she remains anxious, agitated, and unable to sleep. She worries constantly about running out of benzodiazepines, which are “the only medication that helps me.” At the time of evaluation, her medications are venlafaxine ER 150 mg/d, lorazepam 1 mg 3 times daily and 2 mg at bedtime, and buspirone 15 mg 3 times daily, which she admits to not taking. She is overweight and does not exercise. She spends her days snacking and watching television. She can’t settle down enough to read and feels overwhelmed most of the time. Her adult children won’t allow her to babysit their young children because she dozes during the day.

Ms. D has a strong family history of psychiatric illness, including a father with bipolar I disorder and alcohol use disorder and a sister with schizoaffective disorder. Ms. D has never felt overtly manic, but has spent most of her life feeling depressed, anxious, and hopeless, and at times she has wished she was dead. She has had poor responses to many antidepressants, with transient euphoria followed by more anxiety.

Continue to: Rather than major depressive disorder...

Rather than major depressive disorder or GAD, Ms. D’s symptoms better meet the criteria for bipolar II disorder. She agrees to a slow taper of venlafaxine and a slow increase of divalproex, starting with 125 mg each evening. While taking venlafaxine 75 mg/d and divalproex 375 mg/d, she experiences distinct improvement in anxiety and agitation, which further improve after venlafaxine is stopped and divalproex is increased to 750 mg in the evening. She finds that she forgets daytime doses of lorazepam but depends on it to fall asleep. While taking quetiapine 50 mg and lorazepam 1 mg at bedtime, Ms. D reports sleeping soundly and feeling alert in the morning. Over several weeks, she tapers lorazepam slowly by 0.5 mg every 2 weeks. She finds she needs a higher dose of quetiapine to stay asleep, eventually requiring 400 mg each night. Ms. D says overall she feels better but is distressed because she has gained 25 lbs since starting divalproex and quetiapine.

To avoid further increases in quetiapine and maintain its sedating effect, Ms. D is switched to an alternating schedule of clonazepam 1.5 mg for 2 nights and quetiapine 300 mg for 3 nights. She agrees to begin exercising by walking in her neighborhood daily, and gradually increases this to 1 hour per day. After starting to exercise regularly, she finds she is oversedated by quetiapine at night, so she is gradually decreased to a dose of 150 mg, while still alternating with clonazepam 1.5 mg. Ms. D loses most of the weight she had gained and begins volunteering as a reading coach in the elementary school in her neighborhood.

Bottom Line

Patients with chronic insomnia can often maintain adequate sedation without developing tolerance to benzodiazepines or tachyphylaxis with nonsedating agents by using 2 sleep medications that have different mechanisms of action on an alternating schedule.

Related Resources

• Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2): 307-349. doi:10.5664/jcsm.6470
• Muppavarapu K, Muthukanagaraj M, Saeed SA. Cognitive-behavioral therapy for insomnia: a review of 8 studies. Current Psychiatry. 2020;19(9):40-46. doi:10.12788/cp.0040

Drug Brand Names

Alprazolam • Xanax
Armodafinil • Nuvigil
Atomoxetine • Strattera
Bupropion • Wellbutrin
Clonazepam • Klonopin
Diazepam • Valium
Divalproex • Depakote
Doxepin • Sinequan
Escitalopram • Lexapro
Eszopiclone • Lunesta
Lorazepam • Ativan
Lurasidone • Latuda
Methylphenidate • Concerta
Mirtazapine • Remeron
Modafinil • Provigil
Olanzapine • Zyprexa
Quetiapine • Seroquel
Temazepam • Restoril
Trazodone • Desyrel
Triazolam • Halcion
Venlafaxine • Effexor
Zaleplon • Sonata
Zolpidem • Ambien

Good riddance COVID-19 pandemic? Alas, that’s wishful thinking.

Many assume the pandemic is in our rearview mirror, but its biological, psychological, and social impacts continue to unfold. Its repercussions are etched into our brain, mind, emotions, behaviors, cognition, and outlook on life. Welcome to Pandemic 2.0.

Think of people who survive a heart attack. They experience multiple changes. Their initial ephemeral thrill of beating death is rapidly tempered with anxiety and worry about a future myocardial infarction and health issues in general. They become more risk-averse and more prone to dysphoria, irritability, and impatience. These individuals adopt a healthy lifestyle (diet and exercise), which they had neglected before. They develop more disciplined personality traits, feel a greater appreciation for being alive, and develop a closer affinity to family and friends. Simple things they had overlooked become more meaningful. They reevaluate their life goals, including career vs personal fulfilment. Some may overindulge in pleasurable activities in case their heart fails again. Some of those changes may be abrupt or transient, while others may become permanent features of their lives. And some may seek psychotherapy, which they may never have considered before.

The pandemic is the equivalent of a “societal cardiac arrest.” Its immediate impact was devastating. Bustling cities suddenly became ghost towns. Schools were closed, and children were locked at home with their parents, who were laid off. Businesses shut down; the economy tanked. Anxiety about being infected and dying skyrocketed, triggering a universal acute stress reaction that worsened the mental health of the population, but especially of the millions with preexisting psychiatric disorders. Routine medical and dental care stopped. Television and social media disseminated alarming updates about massive intensive care unit admissions and morgues overflowing with corpses of COVID-19 victims. Posttraumatic stress disorder (PTSD) was brewing across the nation as everyone faced this life-threatening pandemic.

The warp-speed development of vaccines for COVID-19 was equivalent to a defibrillator for the societal asystole, but the turmoil continued among the frazzled population. Some refused the vaccine due to conspiracy theories about their dangerous adverse effects. Employees in the private sector, state and federal government, and even the military who refused the mandatory vaccination lost their jobs. Controversy about shuttering schools and depriving children of face-to-face learning and socializing prompted some states to keep schools open, in contrast to most other states. Anger escalated about wearing masks, social distancing, and avoiding gatherings such as at restaurants or houses of worship. Cynicism and mistrust sprouted about the competence and reliability of health “experts” due to some conflicting signals, precluding wide adherence to medical advice.

The lingering effects of the COVID-19 pandemic

Those were the immediate repercussions of the pandemic. But what are its lingering effects? The sequelae extend across 1) the health care system; 2) the mental and emotional wellness of the population; 3) education; 4) work culture; 5) the economy; 6) societal operations; 7) technological and digital transformations; 8) mistrust in various societal institutions; 9) lack of confidence in medical information; and 10) preparedness for another pandemic due to a new strain.

As all psychiatrists know, the demand for mental health services continues to surge well after the pandemic has subsided, straining access to outpatient and inpatient care. Multiple lines of evidence confirm a deterioration in the long-term psychological well-being of children and adolescents because of lockdowns, social isolation, and anxiety about their own health and the health of their loved ones, leading to a serious rise in depression and suicidal behavior.^1-3

Contunue to: Adults who survived pandemic...

Adults who survived the pandemic experienced grief during 2 very stressful years, with no peace of mind or “normal living.” Many began to contemplate the meaning of life and reevaluate the future, waxing more philosophical and embarking on “personal archeology.” The fragility of life suddenly became a ubiquitous epiphany that changed people’s habits. Working from home, which was necessary during the pandemic, became a preferred option for many, and home became an emotional refuge, not just a physical, brick-and-mortar refuge. Millions decided to quit working altogether (the “great resignation”).

Sexual activity declined precipitously during the pandemic for singles (French kissing became “the kiss of death”) but intercourse increased among couples, eventuating in a significant rise in births after the pandemic (a baby boomlet). Sexual interest among college students declined after the pandemic, which may be either due to fear of getting infected or a sublimation of libido to invest the energy in other, less risky activities.

At the societal level, the pandemic’s sequelae included a major shift to virtual communications, not just in health care (telepsychiatry and telemedicine) but also in business. Technology saved the day during the nadir of the pandemic by enabling psychiatrists and psychotherapists to treat their patients remotely. This was not technologically feasible during the past century’s influenza pandemics (1918, 1957, and 1968).

The intellectual and social development of an entire generation of children was stunted due to the COVID-19 pandemic. Consequences will continue to emerge in the years to come and may have ripple effects on this generation’s functioning. This may have particularly affected children of lower socioeconomic status, whose families cannot afford private schools and who are in dire need of good education to put them on the path of upward mobility.

As for adults who did not get infected by COVID-19, they suffered in 2 ways. First, they experienced a certain degree of brain atrophy, which is known to occur in chronic stress. This is attributed to persistent hypercortisolemia, which is toxic to the hippocampus. PTSD is well known to be associated with hippocampal atrophy.⁴ Additionally, a significant proportion of adults who contracted the COVID-19 virus and “recovered” were subsequently diagnosed with “long COVID,” with multiple neuropsychiatric symptoms, including psychosis, mania, depression, and panic attacks, as well as memory impairment and loss of the senses of smell and taste. For these individuals, the pandemic has not subsided; they will carry its neuropsychiatric scars for a long time.

Continue to: Economically, the pandemic...

Economically, the pandemic caused a horrific economic setback in its acute phase, which prompted the government to spend trillions to support the unemployed as well as blighted businesses. The economic sequalae of deficit spending of unprecedented proportions due to the pandemic triggered painful inflation that is ongoing. Interestingly, the numerical terms “billion” and “trillion” lost their loftiness as very huge numbers. Few people realize that counting to a billion (at one number per second) would take 31.7 years, while counting to a trillion would take 31,700 years! The inflationary impact of spending $6 trillion (which would take almost 200,000 years to count) becomes mathematically jarring. And despite the heroic measures to support the economy, some business perished, although others were created, changing the human architecture of the economy.

The pandemic drastically suppressed the “hunting and gathering” instinct of humans and demolished the fabled concept of work ethic. The “great resignation,” coupled with a desire to work from home on a mass scale, led to a glut of vacant office space in many large cities, lowering the value of commercial real estate. Following the pandemic, there was an uptick in moving away from urban areas, reflecting a creative destruction and reversal of a decades-long trend to gravitate to cities to work or live.

There was also political fallout from the pandemic. Staying at home is conducive to overdosing on television and social media, leading to an intensification and ossification of political hyperpartisanship and the further displacement of religious beliefs by passionately entrenched political beliefs. This continues to have seismic effects on political stability and harmony in our country. The pandemic may have instigated new models of national voting, which triggered further political friction.

Other examples of the pandemic’s aftereffects include a shortage of lifeguards and truck drivers, replacing the traditional handshake with a first bump, and increased spending on pleasurable activities (reminiscent of the Roaring 20s following the 1918 influenza pandemic), which may reflect an instinct to “live it up” before another deadly pandemic occurs.

Ironically, as I was finishing writing this article in early September 2023, the government announced that COVID-19 cases were again rising and a new vaccine was available for the new viral “strain.”

Here we go again: as the French saying goes: plus ça change, plus c’est la même chose…

Good riddance COVID-19 pandemic? Alas, that’s wishful thinking.

Many assume the pandemic is in our rearview mirror, but its biological, psychological, and social impacts continue to unfold. Its repercussions are etched into our brain, mind, emotions, behaviors, cognition, and outlook on life. Welcome to Pandemic 2.0.

Think of people who survive a heart attack. They experience multiple changes. Their initial ephemeral thrill of beating death is rapidly tempered with anxiety and worry about a future myocardial infarction and health issues in general. They become more risk-averse and more prone to dysphoria, irritability, and impatience. These individuals adopt a healthy lifestyle (diet and exercise), which they had neglected before. They develop more disciplined personality traits, feel a greater appreciation for being alive, and develop a closer affinity to family and friends. Simple things they had overlooked become more meaningful. They reevaluate their life goals, including career vs personal fulfilment. Some may overindulge in pleasurable activities in case their heart fails again. Some of those changes may be abrupt or transient, while others may become permanent features of their lives. And some may seek psychotherapy, which they may never have considered before.

The pandemic is the equivalent of a “societal cardiac arrest.” Its immediate impact was devastating. Bustling cities suddenly became ghost towns. Schools were closed, and children were locked at home with their parents, who were laid off. Businesses shut down; the economy tanked. Anxiety about being infected and dying skyrocketed, triggering a universal acute stress reaction that worsened the mental health of the population, but especially of the millions with preexisting psychiatric disorders. Routine medical and dental care stopped. Television and social media disseminated alarming updates about massive intensive care unit admissions and morgues overflowing with corpses of COVID-19 victims. Posttraumatic stress disorder (PTSD) was brewing across the nation as everyone faced this life-threatening pandemic.

The warp-speed development of vaccines for COVID-19 was equivalent to a defibrillator for the societal asystole, but the turmoil continued among the frazzled population. Some refused the vaccine due to conspiracy theories about their dangerous adverse effects. Employees in the private sector, state and federal government, and even the military who refused the mandatory vaccination lost their jobs. Controversy about shuttering schools and depriving children of face-to-face learning and socializing prompted some states to keep schools open, in contrast to most other states. Anger escalated about wearing masks, social distancing, and avoiding gatherings such as at restaurants or houses of worship. Cynicism and mistrust sprouted about the competence and reliability of health “experts” due to some conflicting signals, precluding wide adherence to medical advice.

The lingering effects of the COVID-19 pandemic

Those were the immediate repercussions of the pandemic. But what are its lingering effects? The sequelae extend across 1) the health care system; 2) the mental and emotional wellness of the population; 3) education; 4) work culture; 5) the economy; 6) societal operations; 7) technological and digital transformations; 8) mistrust in various societal institutions; 9) lack of confidence in medical information; and 10) preparedness for another pandemic due to a new strain.

As all psychiatrists know, the demand for mental health services continues to surge well after the pandemic has subsided, straining access to outpatient and inpatient care. Multiple lines of evidence confirm a deterioration in the long-term psychological well-being of children and adolescents because of lockdowns, social isolation, and anxiety about their own health and the health of their loved ones, leading to a serious rise in depression and suicidal behavior.^1-3

Contunue to: Adults who survived pandemic...

Adults who survived the pandemic experienced grief during 2 very stressful years, with no peace of mind or “normal living.” Many began to contemplate the meaning of life and reevaluate the future, waxing more philosophical and embarking on “personal archeology.” The fragility of life suddenly became a ubiquitous epiphany that changed people’s habits. Working from home, which was necessary during the pandemic, became a preferred option for many, and home became an emotional refuge, not just a physical, brick-and-mortar refuge. Millions decided to quit working altogether (the “great resignation”).

Sexual activity declined precipitously during the pandemic for singles (French kissing became “the kiss of death”) but intercourse increased among couples, eventuating in a significant rise in births after the pandemic (a baby boomlet). Sexual interest among college students declined after the pandemic, which may be either due to fear of getting infected or a sublimation of libido to invest the energy in other, less risky activities.

At the societal level, the pandemic’s sequelae included a major shift to virtual communications, not just in health care (telepsychiatry and telemedicine) but also in business. Technology saved the day during the nadir of the pandemic by enabling psychiatrists and psychotherapists to treat their patients remotely. This was not technologically feasible during the past century’s influenza pandemics (1918, 1957, and 1968).

The intellectual and social development of an entire generation of children was stunted due to the COVID-19 pandemic. Consequences will continue to emerge in the years to come and may have ripple effects on this generation’s functioning. This may have particularly affected children of lower socioeconomic status, whose families cannot afford private schools and who are in dire need of good education to put them on the path of upward mobility.

As for adults who did not get infected by COVID-19, they suffered in 2 ways. First, they experienced a certain degree of brain atrophy, which is known to occur in chronic stress. This is attributed to persistent hypercortisolemia, which is toxic to the hippocampus. PTSD is well known to be associated with hippocampal atrophy.⁴ Additionally, a significant proportion of adults who contracted the COVID-19 virus and “recovered” were subsequently diagnosed with “long COVID,” with multiple neuropsychiatric symptoms, including psychosis, mania, depression, and panic attacks, as well as memory impairment and loss of the senses of smell and taste. For these individuals, the pandemic has not subsided; they will carry its neuropsychiatric scars for a long time.

Continue to: Economically, the pandemic...

Economically, the pandemic caused a horrific economic setback in its acute phase, which prompted the government to spend trillions to support the unemployed as well as blighted businesses. The economic sequalae of deficit spending of unprecedented proportions due to the pandemic triggered painful inflation that is ongoing. Interestingly, the numerical terms “billion” and “trillion” lost their loftiness as very huge numbers. Few people realize that counting to a billion (at one number per second) would take 31.7 years, while counting to a trillion would take 31,700 years! The inflationary impact of spending $6 trillion (which would take almost 200,000 years to count) becomes mathematically jarring. And despite the heroic measures to support the economy, some business perished, although others were created, changing the human architecture of the economy.

The pandemic drastically suppressed the “hunting and gathering” instinct of humans and demolished the fabled concept of work ethic. The “great resignation,” coupled with a desire to work from home on a mass scale, led to a glut of vacant office space in many large cities, lowering the value of commercial real estate. Following the pandemic, there was an uptick in moving away from urban areas, reflecting a creative destruction and reversal of a decades-long trend to gravitate to cities to work or live.

There was also political fallout from the pandemic. Staying at home is conducive to overdosing on television and social media, leading to an intensification and ossification of political hyperpartisanship and the further displacement of religious beliefs by passionately entrenched political beliefs. This continues to have seismic effects on political stability and harmony in our country. The pandemic may have instigated new models of national voting, which triggered further political friction.

Other examples of the pandemic’s aftereffects include a shortage of lifeguards and truck drivers, replacing the traditional handshake with a first bump, and increased spending on pleasurable activities (reminiscent of the Roaring 20s following the 1918 influenza pandemic), which may reflect an instinct to “live it up” before another deadly pandemic occurs.

Ironically, as I was finishing writing this article in early September 2023, the government announced that COVID-19 cases were again rising and a new vaccine was available for the new viral “strain.”

Here we go again: as the French saying goes: plus ça change, plus c’est la même chose…

Good riddance COVID-19 pandemic? Alas, that’s wishful thinking.

Many assume the pandemic is in our rearview mirror, but its biological, psychological, and social impacts continue to unfold. Its repercussions are etched into our brain, mind, emotions, behaviors, cognition, and outlook on life. Welcome to Pandemic 2.0.

Think of people who survive a heart attack. They experience multiple changes. Their initial ephemeral thrill of beating death is rapidly tempered with anxiety and worry about a future myocardial infarction and health issues in general. They become more risk-averse and more prone to dysphoria, irritability, and impatience. These individuals adopt a healthy lifestyle (diet and exercise), which they had neglected before. They develop more disciplined personality traits, feel a greater appreciation for being alive, and develop a closer affinity to family and friends. Simple things they had overlooked become more meaningful. They reevaluate their life goals, including career vs personal fulfilment. Some may overindulge in pleasurable activities in case their heart fails again. Some of those changes may be abrupt or transient, while others may become permanent features of their lives. And some may seek psychotherapy, which they may never have considered before.

The pandemic is the equivalent of a “societal cardiac arrest.” Its immediate impact was devastating. Bustling cities suddenly became ghost towns. Schools were closed, and children were locked at home with their parents, who were laid off. Businesses shut down; the economy tanked. Anxiety about being infected and dying skyrocketed, triggering a universal acute stress reaction that worsened the mental health of the population, but especially of the millions with preexisting psychiatric disorders. Routine medical and dental care stopped. Television and social media disseminated alarming updates about massive intensive care unit admissions and morgues overflowing with corpses of COVID-19 victims. Posttraumatic stress disorder (PTSD) was brewing across the nation as everyone faced this life-threatening pandemic.

The warp-speed development of vaccines for COVID-19 was equivalent to a defibrillator for the societal asystole, but the turmoil continued among the frazzled population. Some refused the vaccine due to conspiracy theories about their dangerous adverse effects. Employees in the private sector, state and federal government, and even the military who refused the mandatory vaccination lost their jobs. Controversy about shuttering schools and depriving children of face-to-face learning and socializing prompted some states to keep schools open, in contrast to most other states. Anger escalated about wearing masks, social distancing, and avoiding gatherings such as at restaurants or houses of worship. Cynicism and mistrust sprouted about the competence and reliability of health “experts” due to some conflicting signals, precluding wide adherence to medical advice.

The lingering effects of the COVID-19 pandemic

Those were the immediate repercussions of the pandemic. But what are its lingering effects? The sequelae extend across 1) the health care system; 2) the mental and emotional wellness of the population; 3) education; 4) work culture; 5) the economy; 6) societal operations; 7) technological and digital transformations; 8) mistrust in various societal institutions; 9) lack of confidence in medical information; and 10) preparedness for another pandemic due to a new strain.

As all psychiatrists know, the demand for mental health services continues to surge well after the pandemic has subsided, straining access to outpatient and inpatient care. Multiple lines of evidence confirm a deterioration in the long-term psychological well-being of children and adolescents because of lockdowns, social isolation, and anxiety about their own health and the health of their loved ones, leading to a serious rise in depression and suicidal behavior.^1-3

Contunue to: Adults who survived pandemic...

Adults who survived the pandemic experienced grief during 2 very stressful years, with no peace of mind or “normal living.” Many began to contemplate the meaning of life and reevaluate the future, waxing more philosophical and embarking on “personal archeology.” The fragility of life suddenly became a ubiquitous epiphany that changed people’s habits. Working from home, which was necessary during the pandemic, became a preferred option for many, and home became an emotional refuge, not just a physical, brick-and-mortar refuge. Millions decided to quit working altogether (the “great resignation”).

Sexual activity declined precipitously during the pandemic for singles (French kissing became “the kiss of death”) but intercourse increased among couples, eventuating in a significant rise in births after the pandemic (a baby boomlet). Sexual interest among college students declined after the pandemic, which may be either due to fear of getting infected or a sublimation of libido to invest the energy in other, less risky activities.

At the societal level, the pandemic’s sequelae included a major shift to virtual communications, not just in health care (telepsychiatry and telemedicine) but also in business. Technology saved the day during the nadir of the pandemic by enabling psychiatrists and psychotherapists to treat their patients remotely. This was not technologically feasible during the past century’s influenza pandemics (1918, 1957, and 1968).

The intellectual and social development of an entire generation of children was stunted due to the COVID-19 pandemic. Consequences will continue to emerge in the years to come and may have ripple effects on this generation’s functioning. This may have particularly affected children of lower socioeconomic status, whose families cannot afford private schools and who are in dire need of good education to put them on the path of upward mobility.

As for adults who did not get infected by COVID-19, they suffered in 2 ways. First, they experienced a certain degree of brain atrophy, which is known to occur in chronic stress. This is attributed to persistent hypercortisolemia, which is toxic to the hippocampus. PTSD is well known to be associated with hippocampal atrophy.⁴ Additionally, a significant proportion of adults who contracted the COVID-19 virus and “recovered” were subsequently diagnosed with “long COVID,” with multiple neuropsychiatric symptoms, including psychosis, mania, depression, and panic attacks, as well as memory impairment and loss of the senses of smell and taste. For these individuals, the pandemic has not subsided; they will carry its neuropsychiatric scars for a long time.

Continue to: Economically, the pandemic...

Economically, the pandemic caused a horrific economic setback in its acute phase, which prompted the government to spend trillions to support the unemployed as well as blighted businesses. The economic sequalae of deficit spending of unprecedented proportions due to the pandemic triggered painful inflation that is ongoing. Interestingly, the numerical terms “billion” and “trillion” lost their loftiness as very huge numbers. Few people realize that counting to a billion (at one number per second) would take 31.7 years, while counting to a trillion would take 31,700 years! The inflationary impact of spending $6 trillion (which would take almost 200,000 years to count) becomes mathematically jarring. And despite the heroic measures to support the economy, some business perished, although others were created, changing the human architecture of the economy.

The pandemic drastically suppressed the “hunting and gathering” instinct of humans and demolished the fabled concept of work ethic. The “great resignation,” coupled with a desire to work from home on a mass scale, led to a glut of vacant office space in many large cities, lowering the value of commercial real estate. Following the pandemic, there was an uptick in moving away from urban areas, reflecting a creative destruction and reversal of a decades-long trend to gravitate to cities to work or live.

There was also political fallout from the pandemic. Staying at home is conducive to overdosing on television and social media, leading to an intensification and ossification of political hyperpartisanship and the further displacement of religious beliefs by passionately entrenched political beliefs. This continues to have seismic effects on political stability and harmony in our country. The pandemic may have instigated new models of national voting, which triggered further political friction.

Other examples of the pandemic’s aftereffects include a shortage of lifeguards and truck drivers, replacing the traditional handshake with a first bump, and increased spending on pleasurable activities (reminiscent of the Roaring 20s following the 1918 influenza pandemic), which may reflect an instinct to “live it up” before another deadly pandemic occurs.

Ironically, as I was finishing writing this article in early September 2023, the government announced that COVID-19 cases were again rising and a new vaccine was available for the new viral “strain.”

Here we go again: as the French saying goes: plus ça change, plus c’est la même chose…

SECOND OF 2 PARTS

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder characterized by a persistent pattern of inattention, impulsivity, and/or hyperactivity that causes functional impairment.¹ ADHD begins in childhood, continues into adulthood, and has negative consequences in many facets of adult patients’ lives, including their careers, daily functioning, and interpersonal relationships.² According to the National Institute of Health and Care Excellence’s recommendations, both pharmacotherapy and psychotherapy are advised for patients with ADHD.³ Although various pharmacotherapies are advised as first-line treatments for ADHD, they are frequently linked to unfavorable adverse effects, partial responses, chronic residual symptoms, high dropout rates, and issues with addiction.⁴ As a result, there is a need for evidence-based nonpharmacologic therapies.

In a systematic review, Nimmo-Smith et al⁵ found that certain nonpharmacologic treatments can be effective in helping patients with ADHD manage their illness. In clinical and cognitive assessments of ADHD, a recent meta-analysis found that noninvasive brain stimulation had a small but significant effect.⁶ Some evidence suggests that in addition to noninvasive brain stimulation, other nonpharmacologic interventions, including psychoeducation (PE), mindfulness, cognitive-behavioral therapy (CBT), and chronotherapy, can be effective as an adjunct treatment to pharmacotherapy, and possibly as monotherapy.

Part 1 of this 2-part article reviewed 6 randomized controlled trials (RCTs) of pharmacologic interventions for adult ADHD published within the last 5 years.⁷ Part 2 analyzes 6 RCTs of nonpharmacologic treatments for adult ADHD published within the last 5 years (Table^8-13).

1. Leffa DT, Grevet EH, Bau CHD, et al. Transcranial direct current stimulation vs sham for the treatment of inattention in adults with attention-deficit/hyperactivity disorder: the TUNED randomized clinical trial. JAMA Psychiatry. 2022;79(9):847-856. doi:10.1001/jamapsychiatry.2022.2055

Transcranial direct current stimulation (tDCS) uses noninvasive, low-intensity electrical current on the scalp to affect underlying cortical activity.¹⁴ This form of neurostimulation offers an alternative treatment option for when medications fail or are not tolerated, and can be used at home without the direct involvement of a clinician.¹⁴ tDCS as a treatment for ADHD has been increasingly researched, though many studies have been limited by short treatment periods and varied methodological approaches. In a meta-analysis, Westwood et al⁶ found a trend toward improvement on the function of processing speed but not on attention. Leffa et al⁸ examined the efficacy and safety of a 4-week course of home-based tDCS in adult patients with ADHD, specifically looking at reduction in inattention symptoms.

Study design

• This randomized, double-blind, parallel, sham-controlled clinical trial evaluated 64 participants age 18 to 60 from a single center in Brazil who met DSM-5 criteria for combined or primarily inattentive ADHD.
• Inclusion criteria included an inattention score ≥21 on the clinician-administered Adult ADHD Self-report Scale version 1.1 (CASRS). This scale assesses both inattentive symptoms (CASRS-I) and hyperactive-impulsive symptoms (CASRS-HI). Participants were not being treated with stimulants or agreed to undergo a 30-day washout of stimulants prior to the study.
• Exclusion criteria included current moderate to severe depression (Beck Depression Inventory-II [BDI] score >21), current moderate to severe anxiety (Beck Anxiety Inventory [BAI] score ≥21), diagnosis of bipolar disorder (BD) with either a manic or depressive episode in the year prior to study, diagnosis of a psychotic disorder, diagnosis of autism spectrum disorder (ASD), positive screen for substance use, unstable medical condition resulting in poor functionality, pregnant or planning on becoming pregnant within 3 months of the study, not able to use home-based equipment, history of neurosurgery, presence of ferromagnetic metal in the head or presence of implanted medical devices in head/neck region, or history of epilepsy with reported seizures in the year prior to the study.
• Participants were randomized to self-administer real or sham tDCS; the devices looked the same. Participants underwent daily 30-minute sessions using a 2-mA direct constant current for a total of 28 sessions. Sham treatment involved a 30-second ramp-up to 2-mA and a 30-second ramp-down sensation at the beginning, middle, and end of each respective session.
• The primary outcome was a change in symptoms of inattention per CASRS-I. Secondary outcomes were scores on the CASRS-HI, BDI, BAI, and Behavior Rating Inventory of Executive Functions-Adult (BRIEF-A), which evaluates executive function.

Outcomes

• A total of 53 participants used stimulant medications prior to the study and 8 required a washout. The average age was 38.3, and 53% of participants were male.
• For the 55 participants who completed 4 weeks of treatment, the mean number of sessions was 25.2 in the tDCS group and 24.8 in the sham group.
• At the end of Week 4, there was a statistically significant treatment by time interaction in CASRS-I scores in the tDCS group compared to the sham group (18.88 vs 23.63 on final CASRS-I scores; P < .001).
• There were no statistically significant differences in any of the secondary outcomes.

Conclusions/limitations

• This study showed the benefits of 4 weeks of home-based tDCS for managing inattentive symptoms in adults with ADHD. The authors noted that extended treatment of tDCS may incur greater benefit, as this study used a longer treatment course compared to others that have used a shorter duration of treatment (ie, days instead of weeks). Additionally, this study placed the anodal electrode over the right dorsolateral prefrontal cortex (DLPFC) vs over the left DLPFC, because there may be a decrease in activation in the right DLPFC in adults with ADHD undergoing attention tasks.¹⁵
• This study also showed that home-based tDCS can be an easier and more accessible way for patients to receive treatment, as opposed to needing to visit a health care facility.
• Limitations: The dropout rate (although only 2 of 7 participants who dropped out of the active group withdrew due to adverse events), lack of remote monitoring of patients, and restrictive inclusion criteria limit the generalizability of these findings. Additionally, 3 patients in the tDCS group and 7 in the sham group were taking psychotropic medications for anxiety or depression.

Continue to: #2

Previous research has shown that using mindfulness-based approaches can improve ADHD symptoms.^16,17 Hoxhaj et al⁹ looked at the effectiveness of mindfulness awareness practices (MAP) for alleviating ADHD symptoms.

Study design

• This RCT enrolled 81 adults from a German medical center who met DSM-IV criteria for ADHD, were not taking any ADHD medications, and had not undergone any psychotherapeutic treatments in the last 3 months. Participants were randomized to receive MAP (n = 41) or PE (n = 40).
• Exclusion criteria included having a previous diagnosis of schizophrenia, BD I, active substance dependence, ASD, suicidality, self-injurious behavior, or neurologic disorders.
• The MAP group underwent 8 weekly 2.5-hour sessions, plus homework involving meditation and other exercises. The PE group was given information regarding ADHD and management options, including organization and stress management skills.
• Patients were assessed 2 weeks before treatment (T1), at the completion of therapy (T2), and 6 months after the completion of therapy (T3).
• The primary outcome was the change in the blind-observer rated Conner’s Adult ADHD Rating Scales (CAARS) inattention/memory scales from T1 to T2.
• Secondary outcomes included the other CAARS subscales, the Brief Symptom Inventory (BSI), the BDI, the 36-item Short Form Health Survey, and the Five Facet Mindfulness Questionnaire (FFMQ).

Outcomes

• Baseline demographics did not differ between groups other than the MAP group having a significantly higher IQ than the PE group. However, this difference resolved after the final sample was analyzed, as there were 2 dropouts and 7 participants lost to follow-up in the MAP group and 4 dropouts and 4 participants lost to follow-up in the PE group.
• There was no significant difference between the groups in the primary outcome of observer-rated CAARS inattention/memory subscale scores, or other ADHD symptoms per the CAARS.
• However, there was a significant difference within each group on all ADHD subscales of the observer-rated CAARS at T2. Persistent, significant differences were noted for the observer-rated CAARS subscales of self-concept and DSM-IV Inattentive Symptoms, and all CAARS self-report scales to T3.
• Compared to the PE group, there was a significantly larger improvement in the MAP group on scores of the mindfulness parameters of observation and nonreactivity to inner experience.
• There were significant improvements regarding depression per the BDI and global severity per the BSI in both treatment groups, with no differences between the groups.
• At T3, in the MAP group, 3 patients received methylphenidate, 1 received atomoxetine, and 1 received antidepressant medication. In the PE group, 2 patients took methylphenidate, and 2 participants took antidepressants.
• There was a significant difference regarding sex and response, with men experiencing less overall improvement than women.

Conclusions/limitations

• MAP was not superior to PE in terms of changes on CAARS scores, although within each group, both therapies showed improvement over time.
• While there may be gender-specific differences in processing information and coping strategies, future research should examine the differences between men and women with different therapeutic approaches.
• Limitations: This study did not employ a true placebo but instead had 2 active arms. Generalizability is limited due to a lack of certain comorbidities and use of medications.

Continue to: #3

Mindfulness-based cognitive therapy (MBCT) is a form of psychotherapy that combines mindfulness with the principles of CBT. Hepark et al¹⁸ found benefits of MBCT for reducing ADHD symptoms. In a larger, multicenter, single-blind RCT, Janssen et al¹⁰ reviewed the efficacy of MBCT compared to treatment as usual (TAU).

Study design

• A total of 120 participants age ≥18 who met DSM-IV criteria for ADHD were recruited from Dutch clinics and advertisements and randomized to receive MBCT plus TAU (n = 60) or TAU alone (n = 60). There were no significant demographic differences between groups at baseline.
• Exclusion criteria included active depression with psychosis or suicidality, active manic episode, tic disorder with vocal tics, ASD, learning or other cognitive impairments, borderline or antisocial personality disorder, substance dependence, or previous participation in MBCT or other mindfulness-based interventions. Participants also had to be able to complete the questionnaires in Dutch.
• Blinded evaluations were conducted at baseline (T0), at the completion of therapy (T1), 3 months after the completion of therapy (T2), and 6 months after the completion of therapy (T3).
• MBCT included 8 weekly, 2.5-hour sessions and a 6-hour silent session between the sixth and seventh sessions. Patients participated in various meditation techniques with the addition of PE, CBT, and group discussions. They were also instructed to practice guided exercises 6 days/week, for approximately 30 minutes/day.
• The primary outcome was change in ADHD symptoms as assessed by the investigator-rated CAARS (CAARS-INV) at T1.
• Secondary outcomes included change in scores on the CAARS: Screening Version (CAARS-S:SV), BRIEF-A, Five Facet Mindfulness Questionnaire-Short Form (FFMQ-SF), Self-Compassion Scale-Short Form (SCS-SF), Mental Health Continuum-Short Form (MHC-SF), and Outcome Questionnaire (OQ 45.2).

Outcomes

• In the MBCT group, participants who dropped out (n = 9) were less likely to be using ADHD medication at baseline than those who completed the study.
• At T1, the MBCT plus TAU group had significantly less ADHD symptoms on CAARS-INV compared to TAU (d = 0.41, P = .004), with more participants in the MBCT plus TAU group experiencing a symptom reduction ≥30% (24% vs 7%, P = .001) and remission (P = .039).
• The MBCT plus TAU group also had a significant reduction in scores on CAARS-S:SV as well as significant improvement on self-compassion per SCS-SF, mindfulness skills per FFMQ-SF, and positive mental health per MHC-SF, but not on executive functioning per BRIEF-A or general functioning per OQ 45.2.
• Over 6-month follow-up, there continued to be significant improvement in CAARS-INV, CAARS-S:SV, mindfulness skills, self-compassion, and positive mental health in the MBCT plus TAU group compared to TAU. The difference in executive functioning (BRIEF-A) also became significant over time.

Conclusions/limitations

• MBCT plus TAU appears to be effective for reducing ADHD symptoms, both from a clinician-rated and self-reported perspective, with improvements lasting up to 6 months.
• There were also improvements in mindfulness, self-compassion, and positive mental health posttreatment in the MBCT plus TAU group, with improvement in executive functioning seen over the follow-up periods.
• Limitations: The sample was drawn solely from a Dutch population and did not assess the success of blinding.

Continue to: #4

Managing adult ADHD can include PE, but few studies have reviewed the effectiveness of formal clinical PE. PE is “systemic, didactic-psychotherapeutic interventions, which are adequate for informing patients and their relatives about the illness and its treatment, facilitating both an understanding and personally responsible handling of the illness and supporting those afflicted in coping with the disorder.”¹⁹ Selaskowski et al¹¹ investigated the feasibility of using smartphone-assisted PE (SAP) for adults diagnosed with ADHD.

Study design

• Participants were 60 adults age 18 to 65 who met DSM-5 diagnostic criteria for ADHD. They were required to have a working comprehension of the German language and access to an Android-powered smartphone.
• Exclusion criteria included a diagnosis of schizophrenia or other psychotic disorder, antisocial personality disorder, substance use disorder, severe affective disorder, severe neurologic disorder, or initial use or dose change of ADHD medications 2 weeks prior to baseline.
• Participants were randomized to SAP (n = 30) or brochure-assisted PE (BAP) (n = 30). The demographics at baseline were mostly balanced between the groups except for substance abuse (5 in the SAP group vs 0 in the BAP group; P = .022).
• The primary outcome was severity of total ADHD symptoms, which was assessed by blinded evaluations conducted at baseline (T0) and after 8 weekly PE sessions (T1).
• Secondary outcomes included dropout rates, improvement in depressive symptoms as measured by the German BDI-II, improvement in functional impairment as measured by the Weiss Functional Impairment Scale (WFIRS), homework performed, attendance, and obtained PE knowledge.
• Both groups attended 8 weekly 1-hour PE group sessions led by 2 therapists and comprised of 10 participants.

Outcomes

• Only 43 of the 60 initial participants completed the study; 24 in the SAP group and 19 in the BAP group.
• The SAP group experienced a significant symptom improvement of 33.4% from T0 to T1 compared to the BAP group, which experienced a symptom improvement of 17.3% (P = .019).
• ADHD core symptoms considerably decreased in both groups. There was no significant difference between groups (P = .74).
• SAP dramatically improved inattention (P = .019), improved impulsivity (P = .03), and increased completed homework (P < .001), compared to the BAP group.
• There was no significant difference in correctly answered quiz questions or in BDI-II or WFIRS scores.

Conclusions/limitations

• Both SAP and BAP appear to be effective methods for PE, but patients who participated in SAP showed greater improvements than those who participated in BAP.
• Limitations: This study lacked a control intervention that was substantially different from SAP and lacked follow-up. The sample was a mostly German population, participants were required to have smartphone access beforehand, and substance abuse was more common in the SAP group.

Continue to: #5

CBT has demonstrated long-term benefit for the core symptoms of ADHD, comorbid symptoms (anxiety and depression), and social functioning. For ADHD, pharmacotherapies have a bottom-up effect where they increase neurotransmitter concentration, leading to an effect in the prefrontal lobe, whereas psychotherapies affect behavior-related brain activity in the prefrontal lobes, leading to the release of neurotransmitters. Pan et al¹² compared the benefits of CBT plus medication (CBT + M) to CBT alone on core ADHD symptoms, social functioning, and comorbid symptoms.

Study design

• The sample consisted of 124 participants age >18 who had received a diagnosis of adult ADHD according to DSM-IV via Conner’s Adult ADHD Diagnostic Interview and were either outpatients at Peking University Sixth Hospital or participants in a previous RCT (Huang et al²⁰).
• Exclusion criteria included organic mental disorders, high suicide risk in those with major depressive disorder, acute BD episode requiring medication or severe panic disorder or psychotic disorder requiring medication, pervasive developmental disorder, previous or current involvement in other psychological therapies, IQ <90, unstable physical conditions requiring medical treatment, attending <7 CBT sessions, or having serious adverse effects from medication.
• Participants received CBT + M (n = 57) or CBT alone (n = 67); 40 (70.18%) participants in the CBT + M group received methylphenidate hydrochloride controlled-release tablets (average dose 27.45 ± 9.97 mg) and 17 (29.82%) received atomoxetine hydrochloride (average dose 46.35 ± 20.09 mg). There were no significant demographic differences between groups.
• CBT consisted of 12 weekly 2-hour sessions (8 to 12 participants in each group) that were led by 2 trained psychiatrist therapists and focused on behavioral and cognitive strategies.
• Participants in the CBT alone group were drug-naïve and those in CBT + M group were stable on medications.
• The primary outcome was change in ADHD Rating Scale (ADHD-RS) score from baseline to Week 12.
• Secondary outcomes included Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), Self-Esteem Scale (SES), executive functioning (BRIEF-A), and quality of life (World Health Organization Quality of Life-Brief version [WHOQOL-BREF]).

Outcomes

• ADHD-RS total, impulsiveness-hyperactivity subscale, and inattention subscale scores significantly improved in both groups (P < .01). The improvements were greater in the CBT + M group compared to the CBT-only group, but the differences were not statistically significant.
• There was no significant difference between groups in remission rate (P < .689).
• There was a significant improvement in SAS, SES, and SDS scores in both groups (P < .01).
• In terms of the WHOQOL-BREF, the CBT + M group experienced improvements only in the psychological and environmental domains, while the CBT-only group significantly improved across the board. The CBT-only group experienced greater improvement in the physical domain (P < .01).
• Both groups displayed considerable improvements in the Metacognition Index and Global Executive Composite for BRIEF-A. The shift, self-monitor, initiate, working memory, plan/organize, task monitor, and material organization skills significantly improved in the CBT + M group. The only areas where the CBT group significantly improved were initiate, material organization, and working memory. No significant differences in BRIEF-A effectiveness were discovered.

Conclusions/limitations

• CBT is an effective treatment for improving core ADHD symptoms.
• This study was unable to establish that CBT alone was preferable to CBT + M, particularly in terms of core symptoms, emotional symptoms, or self-esteem.
• CBT + M could lead to a greater improvement in executive function than CBT alone.
• Limitations: This study used previous databases rather than RCTs. There was no placebo in the CBT-only group. The findings may not be generalizable because participants had high education levels and IQ. The study lacked follow-up after 12 weeks.

Continue to: #6

Most individuals with ADHD have a delayed circadian rhythm.²¹ Delayed sleep phase syndrome (DSPS) is diagnosed when a persistently delayed circadian rhythm is not brought on by other diseases or medications. ADHD symptoms and circadian rhythm may both benefit from DSPS treatment. A 3-armed randomized clinical parallel-group trial by van Andel et al¹³ investigated the effects of chronotherapy on ADHD symptoms and circadian rhythm.

Study design

• Participants were Dutch-speaking individuals age 18 to 55 who were diagnosed with ADHD and DSPS. They were randomized to receive melatonin 0.5 mg/d (n = 17), placebo (n = 17), or melatonin 0.5 mg/d plus 30 minutes of timed morning bright light therapy (BLT) (n = 15) daily for 3 weeks. There were no significant differences in baseline characteristics between groups except that the melatonin plus BLT group had higher use of oral contraceptives (P = .007).
• This study was completed in the Netherlands with participants from an outpatient adult ADHD clinic.
• Exclusion criteria included epilepsy, psychotic disorders, anxiety or depression requiring acute treatment, alcohol intake >15 units/week in women or >21 units/week in men, ADHD medications, medications affecting sleep, use of drugs, mental retardation, amnestic disorder, dementia, cognitive dysfunction, crossed >2 time zones in the 2 weeks prior to the study, shift work within the previous month, having children disturbing sleep, glaucoma, retinopathy, having BLT within the previous month, pregnancy, lactation, or trying to conceive.
• The study consisted of 3-armed placebo-controlled parallel groups in which 2 were double-blind (melatonin group and placebo group).
• During the first week of treatment, medication was taken 3 hours before dim-light melatonin onset (DLMO) and later advanced to 4 and 5 hours in Week 2 and Week 3, respectively. BLT was used at 20 cm from the eyes for 30 minutes every morning between 7 am and 8 am.
• The primary outcome was DLMO in which radioimmunoassay was used to determine melatonin concentrations. DLMO was used as a marker for internal circadian rhythm.
• The secondary outcome was ADHD symptoms using the Dutch version of the ADHD Rating Scale-IV.
• Evaluations were conducted at baseline (T0), the conclusion of treatment (T1), and 2 weeks after the end of treatment (T2).

Outcomes

• Out of 51 participants, 2 dropped out of the melatonin plus BLT group before baseline, and 3 dropped out of the placebo group before T1.
• At baseline, the average DLMO was 11:43 pm ± 1 hour and 46 minutes, with 77% of participants experiencing DLMO after 11 pm. Melatonin advanced DLMO by 1 hour and 28 minutes (P = .001) and melatonin plus BLT had an advance of 1 hour and 58 minutes (P < .001). DLMO was unaffected by placebo.
• The melatonin group experienced a 14% reduction in ADHD symptoms (P = .038); the placebo and melatonin plus BLT groups did not experience a reduction.
• DLMO and ADHD symptoms returned to baseline 2 weeks after therapy ended.

Conclusions/limitations

• In patients with DSPS and ADHD, low-dose melatonin can improve internal circadian rhythm and decrease ADHD symptoms.
• Melatonin plus BLT was not effective in improving ADHD symptoms or advancing DLMO.
• Limitations: This study used self-reported measures for ADHD symptoms. The generalizability of the findings is limited because the exclusion criteria led to minimal comorbidity. The sample was comprised of a mostly Dutch population.

SECOND OF 2 PARTS

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder characterized by a persistent pattern of inattention, impulsivity, and/or hyperactivity that causes functional impairment.¹ ADHD begins in childhood, continues into adulthood, and has negative consequences in many facets of adult patients’ lives, including their careers, daily functioning, and interpersonal relationships.² According to the National Institute of Health and Care Excellence’s recommendations, both pharmacotherapy and psychotherapy are advised for patients with ADHD.³ Although various pharmacotherapies are advised as first-line treatments for ADHD, they are frequently linked to unfavorable adverse effects, partial responses, chronic residual symptoms, high dropout rates, and issues with addiction.⁴ As a result, there is a need for evidence-based nonpharmacologic therapies.

In a systematic review, Nimmo-Smith et al⁵ found that certain nonpharmacologic treatments can be effective in helping patients with ADHD manage their illness. In clinical and cognitive assessments of ADHD, a recent meta-analysis found that noninvasive brain stimulation had a small but significant effect.⁶ Some evidence suggests that in addition to noninvasive brain stimulation, other nonpharmacologic interventions, including psychoeducation (PE), mindfulness, cognitive-behavioral therapy (CBT), and chronotherapy, can be effective as an adjunct treatment to pharmacotherapy, and possibly as monotherapy.

Part 1 of this 2-part article reviewed 6 randomized controlled trials (RCTs) of pharmacologic interventions for adult ADHD published within the last 5 years.⁷ Part 2 analyzes 6 RCTs of nonpharmacologic treatments for adult ADHD published within the last 5 years (Table^8-13).

1. Leffa DT, Grevet EH, Bau CHD, et al. Transcranial direct current stimulation vs sham for the treatment of inattention in adults with attention-deficit/hyperactivity disorder: the TUNED randomized clinical trial. JAMA Psychiatry. 2022;79(9):847-856. doi:10.1001/jamapsychiatry.2022.2055

Transcranial direct current stimulation (tDCS) uses noninvasive, low-intensity electrical current on the scalp to affect underlying cortical activity.¹⁴ This form of neurostimulation offers an alternative treatment option for when medications fail or are not tolerated, and can be used at home without the direct involvement of a clinician.¹⁴ tDCS as a treatment for ADHD has been increasingly researched, though many studies have been limited by short treatment periods and varied methodological approaches. In a meta-analysis, Westwood et al⁶ found a trend toward improvement on the function of processing speed but not on attention. Leffa et al⁸ examined the efficacy and safety of a 4-week course of home-based tDCS in adult patients with ADHD, specifically looking at reduction in inattention symptoms.

Study design

• This randomized, double-blind, parallel, sham-controlled clinical trial evaluated 64 participants age 18 to 60 from a single center in Brazil who met DSM-5 criteria for combined or primarily inattentive ADHD.
• Inclusion criteria included an inattention score ≥21 on the clinician-administered Adult ADHD Self-report Scale version 1.1 (CASRS). This scale assesses both inattentive symptoms (CASRS-I) and hyperactive-impulsive symptoms (CASRS-HI). Participants were not being treated with stimulants or agreed to undergo a 30-day washout of stimulants prior to the study.
• Exclusion criteria included current moderate to severe depression (Beck Depression Inventory-II [BDI] score >21), current moderate to severe anxiety (Beck Anxiety Inventory [BAI] score ≥21), diagnosis of bipolar disorder (BD) with either a manic or depressive episode in the year prior to study, diagnosis of a psychotic disorder, diagnosis of autism spectrum disorder (ASD), positive screen for substance use, unstable medical condition resulting in poor functionality, pregnant or planning on becoming pregnant within 3 months of the study, not able to use home-based equipment, history of neurosurgery, presence of ferromagnetic metal in the head or presence of implanted medical devices in head/neck region, or history of epilepsy with reported seizures in the year prior to the study.
• Participants were randomized to self-administer real or sham tDCS; the devices looked the same. Participants underwent daily 30-minute sessions using a 2-mA direct constant current for a total of 28 sessions. Sham treatment involved a 30-second ramp-up to 2-mA and a 30-second ramp-down sensation at the beginning, middle, and end of each respective session.
• The primary outcome was a change in symptoms of inattention per CASRS-I. Secondary outcomes were scores on the CASRS-HI, BDI, BAI, and Behavior Rating Inventory of Executive Functions-Adult (BRIEF-A), which evaluates executive function.

Outcomes

• A total of 53 participants used stimulant medications prior to the study and 8 required a washout. The average age was 38.3, and 53% of participants were male.
• For the 55 participants who completed 4 weeks of treatment, the mean number of sessions was 25.2 in the tDCS group and 24.8 in the sham group.
• At the end of Week 4, there was a statistically significant treatment by time interaction in CASRS-I scores in the tDCS group compared to the sham group (18.88 vs 23.63 on final CASRS-I scores; P < .001).
• There were no statistically significant differences in any of the secondary outcomes.

Conclusions/limitations

• This study showed the benefits of 4 weeks of home-based tDCS for managing inattentive symptoms in adults with ADHD. The authors noted that extended treatment of tDCS may incur greater benefit, as this study used a longer treatment course compared to others that have used a shorter duration of treatment (ie, days instead of weeks). Additionally, this study placed the anodal electrode over the right dorsolateral prefrontal cortex (DLPFC) vs over the left DLPFC, because there may be a decrease in activation in the right DLPFC in adults with ADHD undergoing attention tasks.¹⁵
• This study also showed that home-based tDCS can be an easier and more accessible way for patients to receive treatment, as opposed to needing to visit a health care facility.
• Limitations: The dropout rate (although only 2 of 7 participants who dropped out of the active group withdrew due to adverse events), lack of remote monitoring of patients, and restrictive inclusion criteria limit the generalizability of these findings. Additionally, 3 patients in the tDCS group and 7 in the sham group were taking psychotropic medications for anxiety or depression.

Continue to: #2

Previous research has shown that using mindfulness-based approaches can improve ADHD symptoms.^16,17 Hoxhaj et al⁹ looked at the effectiveness of mindfulness awareness practices (MAP) for alleviating ADHD symptoms.

Study design

• This RCT enrolled 81 adults from a German medical center who met DSM-IV criteria for ADHD, were not taking any ADHD medications, and had not undergone any psychotherapeutic treatments in the last 3 months. Participants were randomized to receive MAP (n = 41) or PE (n = 40).
• Exclusion criteria included having a previous diagnosis of schizophrenia, BD I, active substance dependence, ASD, suicidality, self-injurious behavior, or neurologic disorders.
• The MAP group underwent 8 weekly 2.5-hour sessions, plus homework involving meditation and other exercises. The PE group was given information regarding ADHD and management options, including organization and stress management skills.
• Patients were assessed 2 weeks before treatment (T1), at the completion of therapy (T2), and 6 months after the completion of therapy (T3).
• The primary outcome was the change in the blind-observer rated Conner’s Adult ADHD Rating Scales (CAARS) inattention/memory scales from T1 to T2.
• Secondary outcomes included the other CAARS subscales, the Brief Symptom Inventory (BSI), the BDI, the 36-item Short Form Health Survey, and the Five Facet Mindfulness Questionnaire (FFMQ).

Outcomes

• Baseline demographics did not differ between groups other than the MAP group having a significantly higher IQ than the PE group. However, this difference resolved after the final sample was analyzed, as there were 2 dropouts and 7 participants lost to follow-up in the MAP group and 4 dropouts and 4 participants lost to follow-up in the PE group.
• There was no significant difference between the groups in the primary outcome of observer-rated CAARS inattention/memory subscale scores, or other ADHD symptoms per the CAARS.
• However, there was a significant difference within each group on all ADHD subscales of the observer-rated CAARS at T2. Persistent, significant differences were noted for the observer-rated CAARS subscales of self-concept and DSM-IV Inattentive Symptoms, and all CAARS self-report scales to T3.
• Compared to the PE group, there was a significantly larger improvement in the MAP group on scores of the mindfulness parameters of observation and nonreactivity to inner experience.
• There were significant improvements regarding depression per the BDI and global severity per the BSI in both treatment groups, with no differences between the groups.
• At T3, in the MAP group, 3 patients received methylphenidate, 1 received atomoxetine, and 1 received antidepressant medication. In the PE group, 2 patients took methylphenidate, and 2 participants took antidepressants.
• There was a significant difference regarding sex and response, with men experiencing less overall improvement than women.

Conclusions/limitations

• MAP was not superior to PE in terms of changes on CAARS scores, although within each group, both therapies showed improvement over time.
• While there may be gender-specific differences in processing information and coping strategies, future research should examine the differences between men and women with different therapeutic approaches.
• Limitations: This study did not employ a true placebo but instead had 2 active arms. Generalizability is limited due to a lack of certain comorbidities and use of medications.

Continue to: #3

Mindfulness-based cognitive therapy (MBCT) is a form of psychotherapy that combines mindfulness with the principles of CBT. Hepark et al¹⁸ found benefits of MBCT for reducing ADHD symptoms. In a larger, multicenter, single-blind RCT, Janssen et al¹⁰ reviewed the efficacy of MBCT compared to treatment as usual (TAU).

Study design

• A total of 120 participants age ≥18 who met DSM-IV criteria for ADHD were recruited from Dutch clinics and advertisements and randomized to receive MBCT plus TAU (n = 60) or TAU alone (n = 60). There were no significant demographic differences between groups at baseline.
• Exclusion criteria included active depression with psychosis or suicidality, active manic episode, tic disorder with vocal tics, ASD, learning or other cognitive impairments, borderline or antisocial personality disorder, substance dependence, or previous participation in MBCT or other mindfulness-based interventions. Participants also had to be able to complete the questionnaires in Dutch.
• Blinded evaluations were conducted at baseline (T0), at the completion of therapy (T1), 3 months after the completion of therapy (T2), and 6 months after the completion of therapy (T3).
• MBCT included 8 weekly, 2.5-hour sessions and a 6-hour silent session between the sixth and seventh sessions. Patients participated in various meditation techniques with the addition of PE, CBT, and group discussions. They were also instructed to practice guided exercises 6 days/week, for approximately 30 minutes/day.
• The primary outcome was change in ADHD symptoms as assessed by the investigator-rated CAARS (CAARS-INV) at T1.
• Secondary outcomes included change in scores on the CAARS: Screening Version (CAARS-S:SV), BRIEF-A, Five Facet Mindfulness Questionnaire-Short Form (FFMQ-SF), Self-Compassion Scale-Short Form (SCS-SF), Mental Health Continuum-Short Form (MHC-SF), and Outcome Questionnaire (OQ 45.2).

Outcomes

• In the MBCT group, participants who dropped out (n = 9) were less likely to be using ADHD medication at baseline than those who completed the study.
• At T1, the MBCT plus TAU group had significantly less ADHD symptoms on CAARS-INV compared to TAU (d = 0.41, P = .004), with more participants in the MBCT plus TAU group experiencing a symptom reduction ≥30% (24% vs 7%, P = .001) and remission (P = .039).
• The MBCT plus TAU group also had a significant reduction in scores on CAARS-S:SV as well as significant improvement on self-compassion per SCS-SF, mindfulness skills per FFMQ-SF, and positive mental health per MHC-SF, but not on executive functioning per BRIEF-A or general functioning per OQ 45.2.
• Over 6-month follow-up, there continued to be significant improvement in CAARS-INV, CAARS-S:SV, mindfulness skills, self-compassion, and positive mental health in the MBCT plus TAU group compared to TAU. The difference in executive functioning (BRIEF-A) also became significant over time.

Conclusions/limitations

• MBCT plus TAU appears to be effective for reducing ADHD symptoms, both from a clinician-rated and self-reported perspective, with improvements lasting up to 6 months.
• There were also improvements in mindfulness, self-compassion, and positive mental health posttreatment in the MBCT plus TAU group, with improvement in executive functioning seen over the follow-up periods.
• Limitations: The sample was drawn solely from a Dutch population and did not assess the success of blinding.

Continue to: #4

Managing adult ADHD can include PE, but few studies have reviewed the effectiveness of formal clinical PE. PE is “systemic, didactic-psychotherapeutic interventions, which are adequate for informing patients and their relatives about the illness and its treatment, facilitating both an understanding and personally responsible handling of the illness and supporting those afflicted in coping with the disorder.”¹⁹ Selaskowski et al¹¹ investigated the feasibility of using smartphone-assisted PE (SAP) for adults diagnosed with ADHD.

Study design

• Participants were 60 adults age 18 to 65 who met DSM-5 diagnostic criteria for ADHD. They were required to have a working comprehension of the German language and access to an Android-powered smartphone.
• Exclusion criteria included a diagnosis of schizophrenia or other psychotic disorder, antisocial personality disorder, substance use disorder, severe affective disorder, severe neurologic disorder, or initial use or dose change of ADHD medications 2 weeks prior to baseline.
• Participants were randomized to SAP (n = 30) or brochure-assisted PE (BAP) (n = 30). The demographics at baseline were mostly balanced between the groups except for substance abuse (5 in the SAP group vs 0 in the BAP group; P = .022).
• The primary outcome was severity of total ADHD symptoms, which was assessed by blinded evaluations conducted at baseline (T0) and after 8 weekly PE sessions (T1).
• Secondary outcomes included dropout rates, improvement in depressive symptoms as measured by the German BDI-II, improvement in functional impairment as measured by the Weiss Functional Impairment Scale (WFIRS), homework performed, attendance, and obtained PE knowledge.
• Both groups attended 8 weekly 1-hour PE group sessions led by 2 therapists and comprised of 10 participants.

Outcomes

• Only 43 of the 60 initial participants completed the study; 24 in the SAP group and 19 in the BAP group.
• The SAP group experienced a significant symptom improvement of 33.4% from T0 to T1 compared to the BAP group, which experienced a symptom improvement of 17.3% (P = .019).
• ADHD core symptoms considerably decreased in both groups. There was no significant difference between groups (P = .74).
• SAP dramatically improved inattention (P = .019), improved impulsivity (P = .03), and increased completed homework (P < .001), compared to the BAP group.
• There was no significant difference in correctly answered quiz questions or in BDI-II or WFIRS scores.

Conclusions/limitations

• Both SAP and BAP appear to be effective methods for PE, but patients who participated in SAP showed greater improvements than those who participated in BAP.
• Limitations: This study lacked a control intervention that was substantially different from SAP and lacked follow-up. The sample was a mostly German population, participants were required to have smartphone access beforehand, and substance abuse was more common in the SAP group.

Continue to: #5

CBT has demonstrated long-term benefit for the core symptoms of ADHD, comorbid symptoms (anxiety and depression), and social functioning. For ADHD, pharmacotherapies have a bottom-up effect where they increase neurotransmitter concentration, leading to an effect in the prefrontal lobe, whereas psychotherapies affect behavior-related brain activity in the prefrontal lobes, leading to the release of neurotransmitters. Pan et al¹² compared the benefits of CBT plus medication (CBT + M) to CBT alone on core ADHD symptoms, social functioning, and comorbid symptoms.

Study design

• The sample consisted of 124 participants age >18 who had received a diagnosis of adult ADHD according to DSM-IV via Conner’s Adult ADHD Diagnostic Interview and were either outpatients at Peking University Sixth Hospital or participants in a previous RCT (Huang et al²⁰).
• Exclusion criteria included organic mental disorders, high suicide risk in those with major depressive disorder, acute BD episode requiring medication or severe panic disorder or psychotic disorder requiring medication, pervasive developmental disorder, previous or current involvement in other psychological therapies, IQ <90, unstable physical conditions requiring medical treatment, attending <7 CBT sessions, or having serious adverse effects from medication.
• Participants received CBT + M (n = 57) or CBT alone (n = 67); 40 (70.18%) participants in the CBT + M group received methylphenidate hydrochloride controlled-release tablets (average dose 27.45 ± 9.97 mg) and 17 (29.82%) received atomoxetine hydrochloride (average dose 46.35 ± 20.09 mg). There were no significant demographic differences between groups.
• CBT consisted of 12 weekly 2-hour sessions (8 to 12 participants in each group) that were led by 2 trained psychiatrist therapists and focused on behavioral and cognitive strategies.
• Participants in the CBT alone group were drug-naïve and those in CBT + M group were stable on medications.
• The primary outcome was change in ADHD Rating Scale (ADHD-RS) score from baseline to Week 12.
• Secondary outcomes included Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), Self-Esteem Scale (SES), executive functioning (BRIEF-A), and quality of life (World Health Organization Quality of Life-Brief version [WHOQOL-BREF]).

Outcomes

• ADHD-RS total, impulsiveness-hyperactivity subscale, and inattention subscale scores significantly improved in both groups (P < .01). The improvements were greater in the CBT + M group compared to the CBT-only group, but the differences were not statistically significant.
• There was no significant difference between groups in remission rate (P < .689).
• There was a significant improvement in SAS, SES, and SDS scores in both groups (P < .01).
• In terms of the WHOQOL-BREF, the CBT + M group experienced improvements only in the psychological and environmental domains, while the CBT-only group significantly improved across the board. The CBT-only group experienced greater improvement in the physical domain (P < .01).
• Both groups displayed considerable improvements in the Metacognition Index and Global Executive Composite for BRIEF-A. The shift, self-monitor, initiate, working memory, plan/organize, task monitor, and material organization skills significantly improved in the CBT + M group. The only areas where the CBT group significantly improved were initiate, material organization, and working memory. No significant differences in BRIEF-A effectiveness were discovered.

Conclusions/limitations

• CBT is an effective treatment for improving core ADHD symptoms.
• This study was unable to establish that CBT alone was preferable to CBT + M, particularly in terms of core symptoms, emotional symptoms, or self-esteem.
• CBT + M could lead to a greater improvement in executive function than CBT alone.
• Limitations: This study used previous databases rather than RCTs. There was no placebo in the CBT-only group. The findings may not be generalizable because participants had high education levels and IQ. The study lacked follow-up after 12 weeks.

Continue to: #6

Most individuals with ADHD have a delayed circadian rhythm.²¹ Delayed sleep phase syndrome (DSPS) is diagnosed when a persistently delayed circadian rhythm is not brought on by other diseases or medications. ADHD symptoms and circadian rhythm may both benefit from DSPS treatment. A 3-armed randomized clinical parallel-group trial by van Andel et al¹³ investigated the effects of chronotherapy on ADHD symptoms and circadian rhythm.

Study design

• Participants were Dutch-speaking individuals age 18 to 55 who were diagnosed with ADHD and DSPS. They were randomized to receive melatonin 0.5 mg/d (n = 17), placebo (n = 17), or melatonin 0.5 mg/d plus 30 minutes of timed morning bright light therapy (BLT) (n = 15) daily for 3 weeks. There were no significant differences in baseline characteristics between groups except that the melatonin plus BLT group had higher use of oral contraceptives (P = .007).
• This study was completed in the Netherlands with participants from an outpatient adult ADHD clinic.
• Exclusion criteria included epilepsy, psychotic disorders, anxiety or depression requiring acute treatment, alcohol intake >15 units/week in women or >21 units/week in men, ADHD medications, medications affecting sleep, use of drugs, mental retardation, amnestic disorder, dementia, cognitive dysfunction, crossed >2 time zones in the 2 weeks prior to the study, shift work within the previous month, having children disturbing sleep, glaucoma, retinopathy, having BLT within the previous month, pregnancy, lactation, or trying to conceive.
• The study consisted of 3-armed placebo-controlled parallel groups in which 2 were double-blind (melatonin group and placebo group).
• During the first week of treatment, medication was taken 3 hours before dim-light melatonin onset (DLMO) and later advanced to 4 and 5 hours in Week 2 and Week 3, respectively. BLT was used at 20 cm from the eyes for 30 minutes every morning between 7 am and 8 am.
• The primary outcome was DLMO in which radioimmunoassay was used to determine melatonin concentrations. DLMO was used as a marker for internal circadian rhythm.
• The secondary outcome was ADHD symptoms using the Dutch version of the ADHD Rating Scale-IV.
• Evaluations were conducted at baseline (T0), the conclusion of treatment (T1), and 2 weeks after the end of treatment (T2).

Outcomes

• Out of 51 participants, 2 dropped out of the melatonin plus BLT group before baseline, and 3 dropped out of the placebo group before T1.
• At baseline, the average DLMO was 11:43 pm ± 1 hour and 46 minutes, with 77% of participants experiencing DLMO after 11 pm. Melatonin advanced DLMO by 1 hour and 28 minutes (P = .001) and melatonin plus BLT had an advance of 1 hour and 58 minutes (P < .001). DLMO was unaffected by placebo.
• The melatonin group experienced a 14% reduction in ADHD symptoms (P = .038); the placebo and melatonin plus BLT groups did not experience a reduction.
• DLMO and ADHD symptoms returned to baseline 2 weeks after therapy ended.

Conclusions/limitations

• In patients with DSPS and ADHD, low-dose melatonin can improve internal circadian rhythm and decrease ADHD symptoms.
• Melatonin plus BLT was not effective in improving ADHD symptoms or advancing DLMO.
• Limitations: This study used self-reported measures for ADHD symptoms. The generalizability of the findings is limited because the exclusion criteria led to minimal comorbidity. The sample was comprised of a mostly Dutch population.

SECOND OF 2 PARTS

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder characterized by a persistent pattern of inattention, impulsivity, and/or hyperactivity that causes functional impairment.¹ ADHD begins in childhood, continues into adulthood, and has negative consequences in many facets of adult patients’ lives, including their careers, daily functioning, and interpersonal relationships.² According to the National Institute of Health and Care Excellence’s recommendations, both pharmacotherapy and psychotherapy are advised for patients with ADHD.³ Although various pharmacotherapies are advised as first-line treatments for ADHD, they are frequently linked to unfavorable adverse effects, partial responses, chronic residual symptoms, high dropout rates, and issues with addiction.⁴ As a result, there is a need for evidence-based nonpharmacologic therapies.

In a systematic review, Nimmo-Smith et al⁵ found that certain nonpharmacologic treatments can be effective in helping patients with ADHD manage their illness. In clinical and cognitive assessments of ADHD, a recent meta-analysis found that noninvasive brain stimulation had a small but significant effect.⁶ Some evidence suggests that in addition to noninvasive brain stimulation, other nonpharmacologic interventions, including psychoeducation (PE), mindfulness, cognitive-behavioral therapy (CBT), and chronotherapy, can be effective as an adjunct treatment to pharmacotherapy, and possibly as monotherapy.

Part 1 of this 2-part article reviewed 6 randomized controlled trials (RCTs) of pharmacologic interventions for adult ADHD published within the last 5 years.⁷ Part 2 analyzes 6 RCTs of nonpharmacologic treatments for adult ADHD published within the last 5 years (Table^8-13).

1. Leffa DT, Grevet EH, Bau CHD, et al. Transcranial direct current stimulation vs sham for the treatment of inattention in adults with attention-deficit/hyperactivity disorder: the TUNED randomized clinical trial. JAMA Psychiatry. 2022;79(9):847-856. doi:10.1001/jamapsychiatry.2022.2055

Transcranial direct current stimulation (tDCS) uses noninvasive, low-intensity electrical current on the scalp to affect underlying cortical activity.¹⁴ This form of neurostimulation offers an alternative treatment option for when medications fail or are not tolerated, and can be used at home without the direct involvement of a clinician.¹⁴ tDCS as a treatment for ADHD has been increasingly researched, though many studies have been limited by short treatment periods and varied methodological approaches. In a meta-analysis, Westwood et al⁶ found a trend toward improvement on the function of processing speed but not on attention. Leffa et al⁸ examined the efficacy and safety of a 4-week course of home-based tDCS in adult patients with ADHD, specifically looking at reduction in inattention symptoms.

Study design

• This randomized, double-blind, parallel, sham-controlled clinical trial evaluated 64 participants age 18 to 60 from a single center in Brazil who met DSM-5 criteria for combined or primarily inattentive ADHD.
• Inclusion criteria included an inattention score ≥21 on the clinician-administered Adult ADHD Self-report Scale version 1.1 (CASRS). This scale assesses both inattentive symptoms (CASRS-I) and hyperactive-impulsive symptoms (CASRS-HI). Participants were not being treated with stimulants or agreed to undergo a 30-day washout of stimulants prior to the study.
• Exclusion criteria included current moderate to severe depression (Beck Depression Inventory-II [BDI] score >21), current moderate to severe anxiety (Beck Anxiety Inventory [BAI] score ≥21), diagnosis of bipolar disorder (BD) with either a manic or depressive episode in the year prior to study, diagnosis of a psychotic disorder, diagnosis of autism spectrum disorder (ASD), positive screen for substance use, unstable medical condition resulting in poor functionality, pregnant or planning on becoming pregnant within 3 months of the study, not able to use home-based equipment, history of neurosurgery, presence of ferromagnetic metal in the head or presence of implanted medical devices in head/neck region, or history of epilepsy with reported seizures in the year prior to the study.
• Participants were randomized to self-administer real or sham tDCS; the devices looked the same. Participants underwent daily 30-minute sessions using a 2-mA direct constant current for a total of 28 sessions. Sham treatment involved a 30-second ramp-up to 2-mA and a 30-second ramp-down sensation at the beginning, middle, and end of each respective session.
• The primary outcome was a change in symptoms of inattention per CASRS-I. Secondary outcomes were scores on the CASRS-HI, BDI, BAI, and Behavior Rating Inventory of Executive Functions-Adult (BRIEF-A), which evaluates executive function.

Outcomes

• A total of 53 participants used stimulant medications prior to the study and 8 required a washout. The average age was 38.3, and 53% of participants were male.
• For the 55 participants who completed 4 weeks of treatment, the mean number of sessions was 25.2 in the tDCS group and 24.8 in the sham group.
• At the end of Week 4, there was a statistically significant treatment by time interaction in CASRS-I scores in the tDCS group compared to the sham group (18.88 vs 23.63 on final CASRS-I scores; P < .001).
• There were no statistically significant differences in any of the secondary outcomes.

Conclusions/limitations

• This study showed the benefits of 4 weeks of home-based tDCS for managing inattentive symptoms in adults with ADHD. The authors noted that extended treatment of tDCS may incur greater benefit, as this study used a longer treatment course compared to others that have used a shorter duration of treatment (ie, days instead of weeks). Additionally, this study placed the anodal electrode over the right dorsolateral prefrontal cortex (DLPFC) vs over the left DLPFC, because there may be a decrease in activation in the right DLPFC in adults with ADHD undergoing attention tasks.¹⁵
• This study also showed that home-based tDCS can be an easier and more accessible way for patients to receive treatment, as opposed to needing to visit a health care facility.
• Limitations: The dropout rate (although only 2 of 7 participants who dropped out of the active group withdrew due to adverse events), lack of remote monitoring of patients, and restrictive inclusion criteria limit the generalizability of these findings. Additionally, 3 patients in the tDCS group and 7 in the sham group were taking psychotropic medications for anxiety or depression.

Continue to: #2

Previous research has shown that using mindfulness-based approaches can improve ADHD symptoms.^16,17 Hoxhaj et al⁹ looked at the effectiveness of mindfulness awareness practices (MAP) for alleviating ADHD symptoms.

Study design

• This RCT enrolled 81 adults from a German medical center who met DSM-IV criteria for ADHD, were not taking any ADHD medications, and had not undergone any psychotherapeutic treatments in the last 3 months. Participants were randomized to receive MAP (n = 41) or PE (n = 40).
• Exclusion criteria included having a previous diagnosis of schizophrenia, BD I, active substance dependence, ASD, suicidality, self-injurious behavior, or neurologic disorders.
• The MAP group underwent 8 weekly 2.5-hour sessions, plus homework involving meditation and other exercises. The PE group was given information regarding ADHD and management options, including organization and stress management skills.
• Patients were assessed 2 weeks before treatment (T1), at the completion of therapy (T2), and 6 months after the completion of therapy (T3).
• The primary outcome was the change in the blind-observer rated Conner’s Adult ADHD Rating Scales (CAARS) inattention/memory scales from T1 to T2.
• Secondary outcomes included the other CAARS subscales, the Brief Symptom Inventory (BSI), the BDI, the 36-item Short Form Health Survey, and the Five Facet Mindfulness Questionnaire (FFMQ).

Outcomes

• Baseline demographics did not differ between groups other than the MAP group having a significantly higher IQ than the PE group. However, this difference resolved after the final sample was analyzed, as there were 2 dropouts and 7 participants lost to follow-up in the MAP group and 4 dropouts and 4 participants lost to follow-up in the PE group.
• There was no significant difference between the groups in the primary outcome of observer-rated CAARS inattention/memory subscale scores, or other ADHD symptoms per the CAARS.
• However, there was a significant difference within each group on all ADHD subscales of the observer-rated CAARS at T2. Persistent, significant differences were noted for the observer-rated CAARS subscales of self-concept and DSM-IV Inattentive Symptoms, and all CAARS self-report scales to T3.
• Compared to the PE group, there was a significantly larger improvement in the MAP group on scores of the mindfulness parameters of observation and nonreactivity to inner experience.
• There were significant improvements regarding depression per the BDI and global severity per the BSI in both treatment groups, with no differences between the groups.
• At T3, in the MAP group, 3 patients received methylphenidate, 1 received atomoxetine, and 1 received antidepressant medication. In the PE group, 2 patients took methylphenidate, and 2 participants took antidepressants.
• There was a significant difference regarding sex and response, with men experiencing less overall improvement than women.

Conclusions/limitations

• MAP was not superior to PE in terms of changes on CAARS scores, although within each group, both therapies showed improvement over time.
• While there may be gender-specific differences in processing information and coping strategies, future research should examine the differences between men and women with different therapeutic approaches.
• Limitations: This study did not employ a true placebo but instead had 2 active arms. Generalizability is limited due to a lack of certain comorbidities and use of medications.

Continue to: #3

Mindfulness-based cognitive therapy (MBCT) is a form of psychotherapy that combines mindfulness with the principles of CBT. Hepark et al¹⁸ found benefits of MBCT for reducing ADHD symptoms. In a larger, multicenter, single-blind RCT, Janssen et al¹⁰ reviewed the efficacy of MBCT compared to treatment as usual (TAU).

Study design

• A total of 120 participants age ≥18 who met DSM-IV criteria for ADHD were recruited from Dutch clinics and advertisements and randomized to receive MBCT plus TAU (n = 60) or TAU alone (n = 60). There were no significant demographic differences between groups at baseline.
• Exclusion criteria included active depression with psychosis or suicidality, active manic episode, tic disorder with vocal tics, ASD, learning or other cognitive impairments, borderline or antisocial personality disorder, substance dependence, or previous participation in MBCT or other mindfulness-based interventions. Participants also had to be able to complete the questionnaires in Dutch.
• Blinded evaluations were conducted at baseline (T0), at the completion of therapy (T1), 3 months after the completion of therapy (T2), and 6 months after the completion of therapy (T3).
• MBCT included 8 weekly, 2.5-hour sessions and a 6-hour silent session between the sixth and seventh sessions. Patients participated in various meditation techniques with the addition of PE, CBT, and group discussions. They were also instructed to practice guided exercises 6 days/week, for approximately 30 minutes/day.
• The primary outcome was change in ADHD symptoms as assessed by the investigator-rated CAARS (CAARS-INV) at T1.
• Secondary outcomes included change in scores on the CAARS: Screening Version (CAARS-S:SV), BRIEF-A, Five Facet Mindfulness Questionnaire-Short Form (FFMQ-SF), Self-Compassion Scale-Short Form (SCS-SF), Mental Health Continuum-Short Form (MHC-SF), and Outcome Questionnaire (OQ 45.2).

Outcomes

• In the MBCT group, participants who dropped out (n = 9) were less likely to be using ADHD medication at baseline than those who completed the study.
• At T1, the MBCT plus TAU group had significantly less ADHD symptoms on CAARS-INV compared to TAU (d = 0.41, P = .004), with more participants in the MBCT plus TAU group experiencing a symptom reduction ≥30% (24% vs 7%, P = .001) and remission (P = .039).
• The MBCT plus TAU group also had a significant reduction in scores on CAARS-S:SV as well as significant improvement on self-compassion per SCS-SF, mindfulness skills per FFMQ-SF, and positive mental health per MHC-SF, but not on executive functioning per BRIEF-A or general functioning per OQ 45.2.
• Over 6-month follow-up, there continued to be significant improvement in CAARS-INV, CAARS-S:SV, mindfulness skills, self-compassion, and positive mental health in the MBCT plus TAU group compared to TAU. The difference in executive functioning (BRIEF-A) also became significant over time.

Conclusions/limitations

• MBCT plus TAU appears to be effective for reducing ADHD symptoms, both from a clinician-rated and self-reported perspective, with improvements lasting up to 6 months.
• There were also improvements in mindfulness, self-compassion, and positive mental health posttreatment in the MBCT plus TAU group, with improvement in executive functioning seen over the follow-up periods.
• Limitations: The sample was drawn solely from a Dutch population and did not assess the success of blinding.

Continue to: #4

Managing adult ADHD can include PE, but few studies have reviewed the effectiveness of formal clinical PE. PE is “systemic, didactic-psychotherapeutic interventions, which are adequate for informing patients and their relatives about the illness and its treatment, facilitating both an understanding and personally responsible handling of the illness and supporting those afflicted in coping with the disorder.”¹⁹ Selaskowski et al¹¹ investigated the feasibility of using smartphone-assisted PE (SAP) for adults diagnosed with ADHD.

Study design

• Participants were 60 adults age 18 to 65 who met DSM-5 diagnostic criteria for ADHD. They were required to have a working comprehension of the German language and access to an Android-powered smartphone.
• Exclusion criteria included a diagnosis of schizophrenia or other psychotic disorder, antisocial personality disorder, substance use disorder, severe affective disorder, severe neurologic disorder, or initial use or dose change of ADHD medications 2 weeks prior to baseline.
• Participants were randomized to SAP (n = 30) or brochure-assisted PE (BAP) (n = 30). The demographics at baseline were mostly balanced between the groups except for substance abuse (5 in the SAP group vs 0 in the BAP group; P = .022).
• The primary outcome was severity of total ADHD symptoms, which was assessed by blinded evaluations conducted at baseline (T0) and after 8 weekly PE sessions (T1).
• Secondary outcomes included dropout rates, improvement in depressive symptoms as measured by the German BDI-II, improvement in functional impairment as measured by the Weiss Functional Impairment Scale (WFIRS), homework performed, attendance, and obtained PE knowledge.
• Both groups attended 8 weekly 1-hour PE group sessions led by 2 therapists and comprised of 10 participants.

Outcomes

• Only 43 of the 60 initial participants completed the study; 24 in the SAP group and 19 in the BAP group.
• The SAP group experienced a significant symptom improvement of 33.4% from T0 to T1 compared to the BAP group, which experienced a symptom improvement of 17.3% (P = .019).
• ADHD core symptoms considerably decreased in both groups. There was no significant difference between groups (P = .74).
• SAP dramatically improved inattention (P = .019), improved impulsivity (P = .03), and increased completed homework (P < .001), compared to the BAP group.
• There was no significant difference in correctly answered quiz questions or in BDI-II or WFIRS scores.

Conclusions/limitations

• Both SAP and BAP appear to be effective methods for PE, but patients who participated in SAP showed greater improvements than those who participated in BAP.
• Limitations: This study lacked a control intervention that was substantially different from SAP and lacked follow-up. The sample was a mostly German population, participants were required to have smartphone access beforehand, and substance abuse was more common in the SAP group.

Continue to: #5

CBT has demonstrated long-term benefit for the core symptoms of ADHD, comorbid symptoms (anxiety and depression), and social functioning. For ADHD, pharmacotherapies have a bottom-up effect where they increase neurotransmitter concentration, leading to an effect in the prefrontal lobe, whereas psychotherapies affect behavior-related brain activity in the prefrontal lobes, leading to the release of neurotransmitters. Pan et al¹² compared the benefits of CBT plus medication (CBT + M) to CBT alone on core ADHD symptoms, social functioning, and comorbid symptoms.

Study design

• The sample consisted of 124 participants age >18 who had received a diagnosis of adult ADHD according to DSM-IV via Conner’s Adult ADHD Diagnostic Interview and were either outpatients at Peking University Sixth Hospital or participants in a previous RCT (Huang et al²⁰).
• Exclusion criteria included organic mental disorders, high suicide risk in those with major depressive disorder, acute BD episode requiring medication or severe panic disorder or psychotic disorder requiring medication, pervasive developmental disorder, previous or current involvement in other psychological therapies, IQ <90, unstable physical conditions requiring medical treatment, attending <7 CBT sessions, or having serious adverse effects from medication.
• Participants received CBT + M (n = 57) or CBT alone (n = 67); 40 (70.18%) participants in the CBT + M group received methylphenidate hydrochloride controlled-release tablets (average dose 27.45 ± 9.97 mg) and 17 (29.82%) received atomoxetine hydrochloride (average dose 46.35 ± 20.09 mg). There were no significant demographic differences between groups.
• CBT consisted of 12 weekly 2-hour sessions (8 to 12 participants in each group) that were led by 2 trained psychiatrist therapists and focused on behavioral and cognitive strategies.
• Participants in the CBT alone group were drug-naïve and those in CBT + M group were stable on medications.
• The primary outcome was change in ADHD Rating Scale (ADHD-RS) score from baseline to Week 12.
• Secondary outcomes included Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), Self-Esteem Scale (SES), executive functioning (BRIEF-A), and quality of life (World Health Organization Quality of Life-Brief version [WHOQOL-BREF]).

Outcomes

• ADHD-RS total, impulsiveness-hyperactivity subscale, and inattention subscale scores significantly improved in both groups (P < .01). The improvements were greater in the CBT + M group compared to the CBT-only group, but the differences were not statistically significant.
• There was no significant difference between groups in remission rate (P < .689).
• There was a significant improvement in SAS, SES, and SDS scores in both groups (P < .01).
• In terms of the WHOQOL-BREF, the CBT + M group experienced improvements only in the psychological and environmental domains, while the CBT-only group significantly improved across the board. The CBT-only group experienced greater improvement in the physical domain (P < .01).
• Both groups displayed considerable improvements in the Metacognition Index and Global Executive Composite for BRIEF-A. The shift, self-monitor, initiate, working memory, plan/organize, task monitor, and material organization skills significantly improved in the CBT + M group. The only areas where the CBT group significantly improved were initiate, material organization, and working memory. No significant differences in BRIEF-A effectiveness were discovered.

Conclusions/limitations

• CBT is an effective treatment for improving core ADHD symptoms.
• This study was unable to establish that CBT alone was preferable to CBT + M, particularly in terms of core symptoms, emotional symptoms, or self-esteem.
• CBT + M could lead to a greater improvement in executive function than CBT alone.
• Limitations: This study used previous databases rather than RCTs. There was no placebo in the CBT-only group. The findings may not be generalizable because participants had high education levels and IQ. The study lacked follow-up after 12 weeks.

Continue to: #6

Most individuals with ADHD have a delayed circadian rhythm.²¹ Delayed sleep phase syndrome (DSPS) is diagnosed when a persistently delayed circadian rhythm is not brought on by other diseases or medications. ADHD symptoms and circadian rhythm may both benefit from DSPS treatment. A 3-armed randomized clinical parallel-group trial by van Andel et al¹³ investigated the effects of chronotherapy on ADHD symptoms and circadian rhythm.

Study design

• Participants were Dutch-speaking individuals age 18 to 55 who were diagnosed with ADHD and DSPS. They were randomized to receive melatonin 0.5 mg/d (n = 17), placebo (n = 17), or melatonin 0.5 mg/d plus 30 minutes of timed morning bright light therapy (BLT) (n = 15) daily for 3 weeks. There were no significant differences in baseline characteristics between groups except that the melatonin plus BLT group had higher use of oral contraceptives (P = .007).
• This study was completed in the Netherlands with participants from an outpatient adult ADHD clinic.
• Exclusion criteria included epilepsy, psychotic disorders, anxiety or depression requiring acute treatment, alcohol intake >15 units/week in women or >21 units/week in men, ADHD medications, medications affecting sleep, use of drugs, mental retardation, amnestic disorder, dementia, cognitive dysfunction, crossed >2 time zones in the 2 weeks prior to the study, shift work within the previous month, having children disturbing sleep, glaucoma, retinopathy, having BLT within the previous month, pregnancy, lactation, or trying to conceive.
• The study consisted of 3-armed placebo-controlled parallel groups in which 2 were double-blind (melatonin group and placebo group).
• During the first week of treatment, medication was taken 3 hours before dim-light melatonin onset (DLMO) and later advanced to 4 and 5 hours in Week 2 and Week 3, respectively. BLT was used at 20 cm from the eyes for 30 minutes every morning between 7 am and 8 am.
• The primary outcome was DLMO in which radioimmunoassay was used to determine melatonin concentrations. DLMO was used as a marker for internal circadian rhythm.
• The secondary outcome was ADHD symptoms using the Dutch version of the ADHD Rating Scale-IV.
• Evaluations were conducted at baseline (T0), the conclusion of treatment (T1), and 2 weeks after the end of treatment (T2).

Outcomes

• Out of 51 participants, 2 dropped out of the melatonin plus BLT group before baseline, and 3 dropped out of the placebo group before T1.
• At baseline, the average DLMO was 11:43 pm ± 1 hour and 46 minutes, with 77% of participants experiencing DLMO after 11 pm. Melatonin advanced DLMO by 1 hour and 28 minutes (P = .001) and melatonin plus BLT had an advance of 1 hour and 58 minutes (P < .001). DLMO was unaffected by placebo.
• The melatonin group experienced a 14% reduction in ADHD symptoms (P = .038); the placebo and melatonin plus BLT groups did not experience a reduction.
• DLMO and ADHD symptoms returned to baseline 2 weeks after therapy ended.

Conclusions/limitations

• In patients with DSPS and ADHD, low-dose melatonin can improve internal circadian rhythm and decrease ADHD symptoms.
• Melatonin plus BLT was not effective in improving ADHD symptoms or advancing DLMO.
• Limitations: This study used self-reported measures for ADHD symptoms. The generalizability of the findings is limited because the exclusion criteria led to minimal comorbidity. The sample was comprised of a mostly Dutch population.