Article

Spokane, Washington, was supposed to be the center of the Department of Veterans Affairs’ tech reinvention, the first site in the agency’s decade-long project to change its medical records software. But one morning in early March, the latest system malfunction made some clinicians snap.

At Spokane’s Mann-Grandstaff VA Medical Center, the records system — developed by Cerner Corp., based in North Kansas City, Missouri — went down. Staffers, inside the hospital and its outpatient facilities, were back to relying on pen and paper. Computerized schedules were inaccessible. Physicians couldn’t enter new orders or change patients’ medications.

By the next day, the electronic health records were only partially available. Dozens of records remained “sequestered,” meaning that doctors and nurses struggled to update patient charts.

The snafu, the latest in a series at Mann-Grandstaff, heightened Spokane medical staff members’ frustration with a system that has been problematic since it was installed a year and a half ago. The VA said no patients had been harmed because of the problems.

But physicians on the ground there said it’s only a matter of time before serious safety problems — those causing injury or death — emerge, pointing to the program’s ongoing weaknesses amid VA leadership’s full-bore push toward implementation nationwide. One provider said she was glad she didn’t have a relative in Mann-Grandstaff.

The one-two punch of a dangerous outage and staff grievances is the latest setback in the VA’s more than $16 billion effort to upgrade its record-keeping technology. The issues have at times forced clinicians to see fewer patients and file tens of thousands of requests for help to Cerner with patient-safety problems, congressional and agency watchdog reviews show.

If those issues multiply over the vast VA system — which employs more than a quarter-million workers and serves 6.3 million active patients — it could create rampant patient-safety and productivity problems. Despite the VA’s goals of using the technology upgrade to provide seamless records for patients from enlistment in the military until discharge, the doctors and clinicians who spoke to KHN are convinced that the problems experienced in Spokane will be repeated again and again.

The records system, scheduled for deployment at multiple VA facilities in the Pacific Northwest in the coming weeks and months, most recently rolled out at Jonathan M. Wainwright Memorial VA Medical Center in Walla Walla, Washington.

Both Cerner and Mann-Grandstaff officials declined to comment and referred KHN to officials at VA headquarters in Washington, D.C.

“If it’s a total meltdown” in Walla Walla, said Katie Purswell, the American Legion’s director of veterans affairs and rehabilitation, it’s a problem for the department and its decade-long initiative. Initial impressions from staffers are positive, but the issues in Spokane appeared over the course of weeks after the system was turned on.

The distress was particularly acute in early March. On March 2, Cerner turned on a software update to a database containing patient identification information. Problems emerged the next morning. In the record of a patient who was checking in for surgery, staff members discovered incorrect data, including gender information for a different patient. About an hour later, a staffer from the national VA’s medical records office told some clinicians at Mann-Grandstaff to “log out.”

Robert Fischer, Mann-Grandstaff’s medical center director, sent a dire warning later that morning. “Assume all electronic data is corrupted/inaccurate,” Fischer said in an email. He urged clinicians to limit orders for lab work, imaging studies, and medications. The facility shifted to “downtime procedures,” meaning a reliance on paper. 

Some staffers didn’t absorb the late-morning message and continued entering information in the mixed-up records, adding to the stew of erroneous data.

According to information provided to Congress later by the VA, Cerner had informed Mann-Grandstaff of a “complete degradation” the night before — leading to questions from staffers about why it took until late morning the next day to shut down the system. Agency spokesperson Erin Crowe told KHN there wasn’t any delay in notifying staff.

Problems stretched into the following week. Some records — 70 as of March 10, according to a briefing provided to Congress — remained unusable while auditors tried to ascertain what information had been mixed in from other charts. This left clinicians in some instances unable to keep track of patients’ care. Doctors said it became a confusing and chaotic environment. They couldn’t, for example, help patients refill prescriptions.

Members of Congress are concerned — not only about the outage but also VA’s explanations about it. In a letter to agency leadership, the leading Republicans on the House Veterans’ Affairs Committee and the subcommittee overseeing technology, Rep. Mike Bost of Illinois and Rep. Matt Rosendale of Montana, expressed worries the agency was “soft-pedal[ing]” its communications and argued that veterans were misled by assurances that records had been corrected.

The full committee plans to do a deeper examination soon. It has scheduled a closed-door roundtable with VA staffers from Spokane and Walla Walla on April 5.

The outage deepened unhappiness at Mann-Grandstaff. Clinicians there were already frazzled by a deeply buggy system. Downtime was common, a congressional aide told KHN.

A March 17 VA inspector general report documented nearly 39,000 requests for technical help or improvement since the October 2020 deployment of the new records system. Cerner employees often closed requests without resolving the underlying problems, the report said. Mann-Grandstaff staffers became disengaged or devised shortcuts to bypass the malfunctioning software, the inspector general wrote — each a potential root of patient-safety incidents.

The department said the shortcuts — or workarounds — aren’t its policy. “Workarounds are not authorized nor encouraged,” Crowe said.

The Biden administration tried to overhaul the software initiative, putting the program on hiatus before installing new leadership in the medical records office at the end of 2021. But by then, low morale had sunk in. “People in Spokane VA are … demoralized and unhappy,” Rep. Frank Mrvan (D-Ind.), chair of the House subcommittee focused on the VA’s technology modernization programs, told agency leaders during a November congressional hearing. He said staffers told him they felt as though they were beating their heads against a wall to make things function.

Other observers shared Mrvan’s concerns.

Purswell of the American Legion questioned whether appropriate steps are being taken to prepare the Walla Walla facility and its staff for the technology rollout. She asked whether staffers feel as if the Cerner system has been thrust upon them or are excited about the change.

Whether the VA has been persuasive about the benefits of the program is unclear. “I think it’s incumbent on us to demonstrate it’s not a loss,” said Dr. Terry Adirim, the leader of the VA office in charge of implementing the new records technology. “We might have dropped the ball on explaining what a benefit this is.”

Indeed, Adirim conducted a virtual town hall meeting March 21 for veterans in the Walla Walla area — where she was pressed about the problems in Spokane. “If Spokane has been a year figuring this out, why is this moving forward?” one questioner asked, expressing a point made frequently during the call. Adirim said the VA had made “thousands of changes” since the initial rollout.

Medical staffers at the Spokane and Walla Walla VA facilities are part of informal networks sharing their often-negative experiences about the program despite a perception among staff members that dissent will hurt their careers.

Adirim thinks negative feelings can be addressed by stepping up technical support. She also said training programs have been overhauled since the deployment in Spokane. Bottom line: The VA is proceeding.

“People want to revert back to what they did before,” Adirim said, but that’s not going to happen.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Subscribe to KHN's free Morning Briefing.

Spokane, Washington, was supposed to be the center of the Department of Veterans Affairs’ tech reinvention, the first site in the agency’s decade-long project to change its medical records software. But one morning in early March, the latest system malfunction made some clinicians snap.

At Spokane’s Mann-Grandstaff VA Medical Center, the records system — developed by Cerner Corp., based in North Kansas City, Missouri — went down. Staffers, inside the hospital and its outpatient facilities, were back to relying on pen and paper. Computerized schedules were inaccessible. Physicians couldn’t enter new orders or change patients’ medications.

By the next day, the electronic health records were only partially available. Dozens of records remained “sequestered,” meaning that doctors and nurses struggled to update patient charts.

The snafu, the latest in a series at Mann-Grandstaff, heightened Spokane medical staff members’ frustration with a system that has been problematic since it was installed a year and a half ago. The VA said no patients had been harmed because of the problems.

But physicians on the ground there said it’s only a matter of time before serious safety problems — those causing injury or death — emerge, pointing to the program’s ongoing weaknesses amid VA leadership’s full-bore push toward implementation nationwide. One provider said she was glad she didn’t have a relative in Mann-Grandstaff.

The one-two punch of a dangerous outage and staff grievances is the latest setback in the VA’s more than $16 billion effort to upgrade its record-keeping technology. The issues have at times forced clinicians to see fewer patients and file tens of thousands of requests for help to Cerner with patient-safety problems, congressional and agency watchdog reviews show.

If those issues multiply over the vast VA system — which employs more than a quarter-million workers and serves 6.3 million active patients — it could create rampant patient-safety and productivity problems. Despite the VA’s goals of using the technology upgrade to provide seamless records for patients from enlistment in the military until discharge, the doctors and clinicians who spoke to KHN are convinced that the problems experienced in Spokane will be repeated again and again.

The records system, scheduled for deployment at multiple VA facilities in the Pacific Northwest in the coming weeks and months, most recently rolled out at Jonathan M. Wainwright Memorial VA Medical Center in Walla Walla, Washington.

Both Cerner and Mann-Grandstaff officials declined to comment and referred KHN to officials at VA headquarters in Washington, D.C.

“If it’s a total meltdown” in Walla Walla, said Katie Purswell, the American Legion’s director of veterans affairs and rehabilitation, it’s a problem for the department and its decade-long initiative. Initial impressions from staffers are positive, but the issues in Spokane appeared over the course of weeks after the system was turned on.

The distress was particularly acute in early March. On March 2, Cerner turned on a software update to a database containing patient identification information. Problems emerged the next morning. In the record of a patient who was checking in for surgery, staff members discovered incorrect data, including gender information for a different patient. About an hour later, a staffer from the national VA’s medical records office told some clinicians at Mann-Grandstaff to “log out.”

Robert Fischer, Mann-Grandstaff’s medical center director, sent a dire warning later that morning. “Assume all electronic data is corrupted/inaccurate,” Fischer said in an email. He urged clinicians to limit orders for lab work, imaging studies, and medications. The facility shifted to “downtime procedures,” meaning a reliance on paper. 

Some staffers didn’t absorb the late-morning message and continued entering information in the mixed-up records, adding to the stew of erroneous data.

According to information provided to Congress later by the VA, Cerner had informed Mann-Grandstaff of a “complete degradation” the night before — leading to questions from staffers about why it took until late morning the next day to shut down the system. Agency spokesperson Erin Crowe told KHN there wasn’t any delay in notifying staff.

Problems stretched into the following week. Some records — 70 as of March 10, according to a briefing provided to Congress — remained unusable while auditors tried to ascertain what information had been mixed in from other charts. This left clinicians in some instances unable to keep track of patients’ care. Doctors said it became a confusing and chaotic environment. They couldn’t, for example, help patients refill prescriptions.

Members of Congress are concerned — not only about the outage but also VA’s explanations about it. In a letter to agency leadership, the leading Republicans on the House Veterans’ Affairs Committee and the subcommittee overseeing technology, Rep. Mike Bost of Illinois and Rep. Matt Rosendale of Montana, expressed worries the agency was “soft-pedal[ing]” its communications and argued that veterans were misled by assurances that records had been corrected.

The full committee plans to do a deeper examination soon. It has scheduled a closed-door roundtable with VA staffers from Spokane and Walla Walla on April 5.

The outage deepened unhappiness at Mann-Grandstaff. Clinicians there were already frazzled by a deeply buggy system. Downtime was common, a congressional aide told KHN.

A March 17 VA inspector general report documented nearly 39,000 requests for technical help or improvement since the October 2020 deployment of the new records system. Cerner employees often closed requests without resolving the underlying problems, the report said. Mann-Grandstaff staffers became disengaged or devised shortcuts to bypass the malfunctioning software, the inspector general wrote — each a potential root of patient-safety incidents.

The department said the shortcuts — or workarounds — aren’t its policy. “Workarounds are not authorized nor encouraged,” Crowe said.

The Biden administration tried to overhaul the software initiative, putting the program on hiatus before installing new leadership in the medical records office at the end of 2021. But by then, low morale had sunk in. “People in Spokane VA are … demoralized and unhappy,” Rep. Frank Mrvan (D-Ind.), chair of the House subcommittee focused on the VA’s technology modernization programs, told agency leaders during a November congressional hearing. He said staffers told him they felt as though they were beating their heads against a wall to make things function.

Other observers shared Mrvan’s concerns.

Purswell of the American Legion questioned whether appropriate steps are being taken to prepare the Walla Walla facility and its staff for the technology rollout. She asked whether staffers feel as if the Cerner system has been thrust upon them or are excited about the change.

Whether the VA has been persuasive about the benefits of the program is unclear. “I think it’s incumbent on us to demonstrate it’s not a loss,” said Dr. Terry Adirim, the leader of the VA office in charge of implementing the new records technology. “We might have dropped the ball on explaining what a benefit this is.”

Indeed, Adirim conducted a virtual town hall meeting March 21 for veterans in the Walla Walla area — where she was pressed about the problems in Spokane. “If Spokane has been a year figuring this out, why is this moving forward?” one questioner asked, expressing a point made frequently during the call. Adirim said the VA had made “thousands of changes” since the initial rollout.

Medical staffers at the Spokane and Walla Walla VA facilities are part of informal networks sharing their often-negative experiences about the program despite a perception among staff members that dissent will hurt their careers.

Adirim thinks negative feelings can be addressed by stepping up technical support. She also said training programs have been overhauled since the deployment in Spokane. Bottom line: The VA is proceeding.

“People want to revert back to what they did before,” Adirim said, but that’s not going to happen.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Subscribe to KHN's free Morning Briefing.

Spokane, Washington, was supposed to be the center of the Department of Veterans Affairs’ tech reinvention, the first site in the agency’s decade-long project to change its medical records software. But one morning in early March, the latest system malfunction made some clinicians snap.

At Spokane’s Mann-Grandstaff VA Medical Center, the records system — developed by Cerner Corp., based in North Kansas City, Missouri — went down. Staffers, inside the hospital and its outpatient facilities, were back to relying on pen and paper. Computerized schedules were inaccessible. Physicians couldn’t enter new orders or change patients’ medications.

By the next day, the electronic health records were only partially available. Dozens of records remained “sequestered,” meaning that doctors and nurses struggled to update patient charts.

The snafu, the latest in a series at Mann-Grandstaff, heightened Spokane medical staff members’ frustration with a system that has been problematic since it was installed a year and a half ago. The VA said no patients had been harmed because of the problems.

But physicians on the ground there said it’s only a matter of time before serious safety problems — those causing injury or death — emerge, pointing to the program’s ongoing weaknesses amid VA leadership’s full-bore push toward implementation nationwide. One provider said she was glad she didn’t have a relative in Mann-Grandstaff.

The one-two punch of a dangerous outage and staff grievances is the latest setback in the VA’s more than $16 billion effort to upgrade its record-keeping technology. The issues have at times forced clinicians to see fewer patients and file tens of thousands of requests for help to Cerner with patient-safety problems, congressional and agency watchdog reviews show.

If those issues multiply over the vast VA system — which employs more than a quarter-million workers and serves 6.3 million active patients — it could create rampant patient-safety and productivity problems. Despite the VA’s goals of using the technology upgrade to provide seamless records for patients from enlistment in the military until discharge, the doctors and clinicians who spoke to KHN are convinced that the problems experienced in Spokane will be repeated again and again.

The records system, scheduled for deployment at multiple VA facilities in the Pacific Northwest in the coming weeks and months, most recently rolled out at Jonathan M. Wainwright Memorial VA Medical Center in Walla Walla, Washington.

Both Cerner and Mann-Grandstaff officials declined to comment and referred KHN to officials at VA headquarters in Washington, D.C.

“If it’s a total meltdown” in Walla Walla, said Katie Purswell, the American Legion’s director of veterans affairs and rehabilitation, it’s a problem for the department and its decade-long initiative. Initial impressions from staffers are positive, but the issues in Spokane appeared over the course of weeks after the system was turned on.

The distress was particularly acute in early March. On March 2, Cerner turned on a software update to a database containing patient identification information. Problems emerged the next morning. In the record of a patient who was checking in for surgery, staff members discovered incorrect data, including gender information for a different patient. About an hour later, a staffer from the national VA’s medical records office told some clinicians at Mann-Grandstaff to “log out.”

Robert Fischer, Mann-Grandstaff’s medical center director, sent a dire warning later that morning. “Assume all electronic data is corrupted/inaccurate,” Fischer said in an email. He urged clinicians to limit orders for lab work, imaging studies, and medications. The facility shifted to “downtime procedures,” meaning a reliance on paper. 

Some staffers didn’t absorb the late-morning message and continued entering information in the mixed-up records, adding to the stew of erroneous data.

According to information provided to Congress later by the VA, Cerner had informed Mann-Grandstaff of a “complete degradation” the night before — leading to questions from staffers about why it took until late morning the next day to shut down the system. Agency spokesperson Erin Crowe told KHN there wasn’t any delay in notifying staff.

Problems stretched into the following week. Some records — 70 as of March 10, according to a briefing provided to Congress — remained unusable while auditors tried to ascertain what information had been mixed in from other charts. This left clinicians in some instances unable to keep track of patients’ care. Doctors said it became a confusing and chaotic environment. They couldn’t, for example, help patients refill prescriptions.

Members of Congress are concerned — not only about the outage but also VA’s explanations about it. In a letter to agency leadership, the leading Republicans on the House Veterans’ Affairs Committee and the subcommittee overseeing technology, Rep. Mike Bost of Illinois and Rep. Matt Rosendale of Montana, expressed worries the agency was “soft-pedal[ing]” its communications and argued that veterans were misled by assurances that records had been corrected.

The full committee plans to do a deeper examination soon. It has scheduled a closed-door roundtable with VA staffers from Spokane and Walla Walla on April 5.

The outage deepened unhappiness at Mann-Grandstaff. Clinicians there were already frazzled by a deeply buggy system. Downtime was common, a congressional aide told KHN.

A March 17 VA inspector general report documented nearly 39,000 requests for technical help or improvement since the October 2020 deployment of the new records system. Cerner employees often closed requests without resolving the underlying problems, the report said. Mann-Grandstaff staffers became disengaged or devised shortcuts to bypass the malfunctioning software, the inspector general wrote — each a potential root of patient-safety incidents.

The department said the shortcuts — or workarounds — aren’t its policy. “Workarounds are not authorized nor encouraged,” Crowe said.

The Biden administration tried to overhaul the software initiative, putting the program on hiatus before installing new leadership in the medical records office at the end of 2021. But by then, low morale had sunk in. “People in Spokane VA are … demoralized and unhappy,” Rep. Frank Mrvan (D-Ind.), chair of the House subcommittee focused on the VA’s technology modernization programs, told agency leaders during a November congressional hearing. He said staffers told him they felt as though they were beating their heads against a wall to make things function.

Other observers shared Mrvan’s concerns.

Purswell of the American Legion questioned whether appropriate steps are being taken to prepare the Walla Walla facility and its staff for the technology rollout. She asked whether staffers feel as if the Cerner system has been thrust upon them or are excited about the change.

Whether the VA has been persuasive about the benefits of the program is unclear. “I think it’s incumbent on us to demonstrate it’s not a loss,” said Dr. Terry Adirim, the leader of the VA office in charge of implementing the new records technology. “We might have dropped the ball on explaining what a benefit this is.”

Indeed, Adirim conducted a virtual town hall meeting March 21 for veterans in the Walla Walla area — where she was pressed about the problems in Spokane. “If Spokane has been a year figuring this out, why is this moving forward?” one questioner asked, expressing a point made frequently during the call. Adirim said the VA had made “thousands of changes” since the initial rollout.

Medical staffers at the Spokane and Walla Walla VA facilities are part of informal networks sharing their often-negative experiences about the program despite a perception among staff members that dissent will hurt their careers.

Adirim thinks negative feelings can be addressed by stepping up technical support. She also said training programs have been overhauled since the deployment in Spokane. Bottom line: The VA is proceeding.

“People want to revert back to what they did before,” Adirim said, but that’s not going to happen.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Subscribe to KHN's free Morning Briefing.

The Diagnosis: Reactive Perforating Collagenosis

Reactive perforating collagenosis (RPC) may be either acquired or inherited. It is 1 of 4 classical forms of transepithelial elimination, which also includes elastosis perforans serpiginosa (EPS) as well as perforating folliculitis and Kyrle disease. These 4 forms of transepithelial elimination share characteristics of the elimination of altered dermal components through the epidermis.¹ The acquired subtype of RPC frequently occurs in patients with diabetes mellitus and end-stage renal disease,² both present in our patient.

Clinical presentation typically shows pruritic hyperkeratotic papules with a central crater filled with crust that frequently are distributed on the extensor surfaces of the extremities, often in a linear pattern.³ The perforating papules and nodules occasionally may involve the trunk and face.⁴ Histopathologic examination is characterized by the elimination of altered collagen through the epidermis. Established lesions may show a cup-shaped depression of the epidermis filled with a keratin plug. The underlying dermis will show vertically oriented basophilic collagen fibers with focal extrusion through the epidermis, and elastic fibers will be absent.⁵ The exact pathophysiology of this disease is unknown, but it may represent a cutaneous response to superficial trauma caused by intense scratching.⁶

Standard treatment protocols are not well established for this condition, but some evidence shows that a combination of treatments can help ameliorate symptoms, even if they are not curative.⁷ Treatments without strong evidence have included a wide range of topical, systemic, and other therapies. Case series and anecdotal reports have used retinoids, corticosteroids, menthol, antibiotics, allopurinol antihistamines, cryotherapy, and lasers.⁸ One case was treated with a combination of narrowband UVB phototherapy and doxycycline with resolution in approximately 6 weeks.⁹ Other cases have been cured using triple therapy with antihistamines, topical or injected steroids, and emollients or oral antibiotics.⁷ Evidence shows that there may be benefit to combining multiple different treatment types that target pruritus, inflammation, and collagen damage.^7,9 This disease usually cannot be cured, but it may be improved by the available treatments.

The differential diagnosis includes delusional parasitosis, EPS, perforating folliculitis, and prurigo nodularis. Delusional parasitosis also can be characterized by excoriated plaques and a sensation of parasites infesting the skin, as our patient described.¹⁰ However, it can be differentiated from RPC by the fact that it is a diagnosis of exclusion, which would not have the histopathologic findings of the elimination of collagen from the epidermis, as was demonstrated in our patient.¹¹ Elastosis perforans serpiginosa is in the same family of perforating diseases as RPC; however, EPS typically appears in children or young adults and often is associated with other genetic disorders. Physical examination in a patient with EPS would reveal keratotic papules in a serpiginous pattern, whereas our patient had discrete lesions without any serpiginous pattern. The histopathologic appearance of EPS would reveal plugs of elastic fibers rather than collagen fibers, as was demonstrated in our patient.⁸ Perforating folliculitis, while also demonstrating transepithelial elimination similar to RPC, would appear as erythematous follicular papules with small central keratotic plugs and histopathologic findings of a widely dilated follicle with a mass of keratotic debris.¹² Prurigo nodularis would appear as dome-shaped papulonodules with varying degrees of scale, crust, and erosion, with a histopathologic appearance of hyperplasia and thick hyperkeratosis.¹¹

Overall, the histopathology is paramount in differentiating RPC from the alternative diagnoses, with the extrusion of collagen from the epidermis not being seen in these other conditions. The coupling of the medical history (type 2 diabetes mellitus and end-stage renal disease) with the clinical presentation and skin biopsy findings confirmed the diagnosis of RPC.

The Diagnosis: Reactive Perforating Collagenosis

Reactive perforating collagenosis (RPC) may be either acquired or inherited. It is 1 of 4 classical forms of transepithelial elimination, which also includes elastosis perforans serpiginosa (EPS) as well as perforating folliculitis and Kyrle disease. These 4 forms of transepithelial elimination share characteristics of the elimination of altered dermal components through the epidermis.¹ The acquired subtype of RPC frequently occurs in patients with diabetes mellitus and end-stage renal disease,² both present in our patient.

Clinical presentation typically shows pruritic hyperkeratotic papules with a central crater filled with crust that frequently are distributed on the extensor surfaces of the extremities, often in a linear pattern.³ The perforating papules and nodules occasionally may involve the trunk and face.⁴ Histopathologic examination is characterized by the elimination of altered collagen through the epidermis. Established lesions may show a cup-shaped depression of the epidermis filled with a keratin plug. The underlying dermis will show vertically oriented basophilic collagen fibers with focal extrusion through the epidermis, and elastic fibers will be absent.⁵ The exact pathophysiology of this disease is unknown, but it may represent a cutaneous response to superficial trauma caused by intense scratching.⁶

Standard treatment protocols are not well established for this condition, but some evidence shows that a combination of treatments can help ameliorate symptoms, even if they are not curative.⁷ Treatments without strong evidence have included a wide range of topical, systemic, and other therapies. Case series and anecdotal reports have used retinoids, corticosteroids, menthol, antibiotics, allopurinol antihistamines, cryotherapy, and lasers.⁸ One case was treated with a combination of narrowband UVB phototherapy and doxycycline with resolution in approximately 6 weeks.⁹ Other cases have been cured using triple therapy with antihistamines, topical or injected steroids, and emollients or oral antibiotics.⁷ Evidence shows that there may be benefit to combining multiple different treatment types that target pruritus, inflammation, and collagen damage.^7,9 This disease usually cannot be cured, but it may be improved by the available treatments.

The differential diagnosis includes delusional parasitosis, EPS, perforating folliculitis, and prurigo nodularis. Delusional parasitosis also can be characterized by excoriated plaques and a sensation of parasites infesting the skin, as our patient described.¹⁰ However, it can be differentiated from RPC by the fact that it is a diagnosis of exclusion, which would not have the histopathologic findings of the elimination of collagen from the epidermis, as was demonstrated in our patient.¹¹ Elastosis perforans serpiginosa is in the same family of perforating diseases as RPC; however, EPS typically appears in children or young adults and often is associated with other genetic disorders. Physical examination in a patient with EPS would reveal keratotic papules in a serpiginous pattern, whereas our patient had discrete lesions without any serpiginous pattern. The histopathologic appearance of EPS would reveal plugs of elastic fibers rather than collagen fibers, as was demonstrated in our patient.⁸ Perforating folliculitis, while also demonstrating transepithelial elimination similar to RPC, would appear as erythematous follicular papules with small central keratotic plugs and histopathologic findings of a widely dilated follicle with a mass of keratotic debris.¹² Prurigo nodularis would appear as dome-shaped papulonodules with varying degrees of scale, crust, and erosion, with a histopathologic appearance of hyperplasia and thick hyperkeratosis.¹¹

Overall, the histopathology is paramount in differentiating RPC from the alternative diagnoses, with the extrusion of collagen from the epidermis not being seen in these other conditions. The coupling of the medical history (type 2 diabetes mellitus and end-stage renal disease) with the clinical presentation and skin biopsy findings confirmed the diagnosis of RPC.

The Diagnosis: Reactive Perforating Collagenosis

Reactive perforating collagenosis (RPC) may be either acquired or inherited. It is 1 of 4 classical forms of transepithelial elimination, which also includes elastosis perforans serpiginosa (EPS) as well as perforating folliculitis and Kyrle disease. These 4 forms of transepithelial elimination share characteristics of the elimination of altered dermal components through the epidermis.¹ The acquired subtype of RPC frequently occurs in patients with diabetes mellitus and end-stage renal disease,² both present in our patient.

Clinical presentation typically shows pruritic hyperkeratotic papules with a central crater filled with crust that frequently are distributed on the extensor surfaces of the extremities, often in a linear pattern.³ The perforating papules and nodules occasionally may involve the trunk and face.⁴ Histopathologic examination is characterized by the elimination of altered collagen through the epidermis. Established lesions may show a cup-shaped depression of the epidermis filled with a keratin plug. The underlying dermis will show vertically oriented basophilic collagen fibers with focal extrusion through the epidermis, and elastic fibers will be absent.⁵ The exact pathophysiology of this disease is unknown, but it may represent a cutaneous response to superficial trauma caused by intense scratching.⁶

Standard treatment protocols are not well established for this condition, but some evidence shows that a combination of treatments can help ameliorate symptoms, even if they are not curative.⁷ Treatments without strong evidence have included a wide range of topical, systemic, and other therapies. Case series and anecdotal reports have used retinoids, corticosteroids, menthol, antibiotics, allopurinol antihistamines, cryotherapy, and lasers.⁸ One case was treated with a combination of narrowband UVB phototherapy and doxycycline with resolution in approximately 6 weeks.⁹ Other cases have been cured using triple therapy with antihistamines, topical or injected steroids, and emollients or oral antibiotics.⁷ Evidence shows that there may be benefit to combining multiple different treatment types that target pruritus, inflammation, and collagen damage.^7,9 This disease usually cannot be cured, but it may be improved by the available treatments.

The differential diagnosis includes delusional parasitosis, EPS, perforating folliculitis, and prurigo nodularis. Delusional parasitosis also can be characterized by excoriated plaques and a sensation of parasites infesting the skin, as our patient described.¹⁰ However, it can be differentiated from RPC by the fact that it is a diagnosis of exclusion, which would not have the histopathologic findings of the elimination of collagen from the epidermis, as was demonstrated in our patient.¹¹ Elastosis perforans serpiginosa is in the same family of perforating diseases as RPC; however, EPS typically appears in children or young adults and often is associated with other genetic disorders. Physical examination in a patient with EPS would reveal keratotic papules in a serpiginous pattern, whereas our patient had discrete lesions without any serpiginous pattern. The histopathologic appearance of EPS would reveal plugs of elastic fibers rather than collagen fibers, as was demonstrated in our patient.⁸ Perforating folliculitis, while also demonstrating transepithelial elimination similar to RPC, would appear as erythematous follicular papules with small central keratotic plugs and histopathologic findings of a widely dilated follicle with a mass of keratotic debris.¹² Prurigo nodularis would appear as dome-shaped papulonodules with varying degrees of scale, crust, and erosion, with a histopathologic appearance of hyperplasia and thick hyperkeratosis.¹¹

Overall, the histopathology is paramount in differentiating RPC from the alternative diagnoses, with the extrusion of collagen from the epidermis not being seen in these other conditions. The coupling of the medical history (type 2 diabetes mellitus and end-stage renal disease) with the clinical presentation and skin biopsy findings confirmed the diagnosis of RPC.

Dupilumab is a subcutaneous injection therapy that inhibits the interleukin 4 receptor alpha subunit. It has been approved in the United States for the treatment of adults with moderate-to-severe AD since 2017 and has since been approved for children and adolescents older than 6 years. Many real-world studies of the effectiveness of dupilumab have been published over the past few years. Kojanova and colleagues reported findings from a retrospective, multicenter study of 360 adults with severe AD who received dupilumab. They found that a high proportion of patients achieved a 75% improvement in the Eczema Area and Severity Index (EASI-75) at week 16 (66.6%), 1 year (89.5%), and 2 years (95.8%). Drug persistence rates were very high (> 90%) throughout the 2 years of therapy, suggesting that dupilumab was effective and well-tolerated.

Dupilumab was previously found to be associated with increased conjunctivitis in clinical trials and real-world studies. Schneeweiss and colleagues conducted a population-based longitudinal study of 5,004,117 patients with AD who newly initiated dupilumab, methotrexate, mycophenolate, and cyclosporine. They found that the risk of developing conjunctivitis diagnosed in clinical practice within 6 months of treatment initiation was approximately double with dupilumab compared with methotrexate, mycophenolate, or cyclosporine. Interestingly, comorbid asthma was found to be a risk factor for conjunctivitis in dupilumab initiators. This study provides insight into how commonly clinically significant conjunctivitis occurs with dupilumab treatment. Of note, the study results may underestimate the incidence of conjunctivitis because milder cases may go undetected.

Upadacitinib is an oral selective Janus kinase (JAK) 1 inhibitor that was approved in the United States in 2022 for the treatment of moderate-to-severe AD. Simpson and colleagues reported on the long-term efficacy and safety of oral upadacitinib from the phase 3 double-blind, randomized controlled trials Measure Up 1 and Measure Up 2 in adolescents and adults with moderate-to-severe atopic dermatitis ho had an inadequate response to topical therapy. The initial phase of the Measure Up 1 and Measure Up 2 studies was 16 weeks in duration, with a placebo control group. At week 16, patients who received 15 or 30 mg upadacitinib in the initial 16 weeks of the study continued to receive that dose. Patients who received placebo in the initial 16 weeks were randomly assigned to receive oral 15 mg or 30 mg upadacitinib daily. So, in the long run, all patients received upadacitinib in the second phase of the study but were blinded to the dose they were receiving. The results from the first 16 weeks of treatment were previously published. Simpson and colleagues reported on the results up to week 52 from the second phase of the study. They showed that at week 52, 82.0% and 79.1% of patients in Measure Up 1 and Measure Up 2 achieved a 75% improvement in EASI-75 when continuing on 15 mg upadacitinib and 84.9% and 84.3% in patients continuing 30 mg upadacitinib, respectively. More than 80% of patients who switched from placebo to upadacitinib at week 16 achieved EASI-75 at week 52. No safety signals were observed in this phase of the study that were not previously observed in other studies of upadacitinib for atopic dermatitis and other indications (rheumatoid arthritis and psoriatic arthritis). These results indicate that upadacitinib has durable efficacy with long-term treatment in moderate-to-severe AD. These studies are ongoing, and I look forward to future results reporting for even longer-term treatment.

It is an exciting time in dermatology with the arrival of multiple novel therapies for atopic dermatitis. The field has already benefited so much by the tremendous interest and research effort into understanding how to best manage this disease. With so many more treatments in the pipeline, perhaps the best is yet to come.

Dupilumab is a subcutaneous injection therapy that inhibits the interleukin 4 receptor alpha subunit. It has been approved in the United States for the treatment of adults with moderate-to-severe AD since 2017 and has since been approved for children and adolescents older than 6 years. Many real-world studies of the effectiveness of dupilumab have been published over the past few years. Kojanova and colleagues reported findings from a retrospective, multicenter study of 360 adults with severe AD who received dupilumab. They found that a high proportion of patients achieved a 75% improvement in the Eczema Area and Severity Index (EASI-75) at week 16 (66.6%), 1 year (89.5%), and 2 years (95.8%). Drug persistence rates were very high (> 90%) throughout the 2 years of therapy, suggesting that dupilumab was effective and well-tolerated.

Dupilumab was previously found to be associated with increased conjunctivitis in clinical trials and real-world studies. Schneeweiss and colleagues conducted a population-based longitudinal study of 5,004,117 patients with AD who newly initiated dupilumab, methotrexate, mycophenolate, and cyclosporine. They found that the risk of developing conjunctivitis diagnosed in clinical practice within 6 months of treatment initiation was approximately double with dupilumab compared with methotrexate, mycophenolate, or cyclosporine. Interestingly, comorbid asthma was found to be a risk factor for conjunctivitis in dupilumab initiators. This study provides insight into how commonly clinically significant conjunctivitis occurs with dupilumab treatment. Of note, the study results may underestimate the incidence of conjunctivitis because milder cases may go undetected.

Upadacitinib is an oral selective Janus kinase (JAK) 1 inhibitor that was approved in the United States in 2022 for the treatment of moderate-to-severe AD. Simpson and colleagues reported on the long-term efficacy and safety of oral upadacitinib from the phase 3 double-blind, randomized controlled trials Measure Up 1 and Measure Up 2 in adolescents and adults with moderate-to-severe atopic dermatitis ho had an inadequate response to topical therapy. The initial phase of the Measure Up 1 and Measure Up 2 studies was 16 weeks in duration, with a placebo control group. At week 16, patients who received 15 or 30 mg upadacitinib in the initial 16 weeks of the study continued to receive that dose. Patients who received placebo in the initial 16 weeks were randomly assigned to receive oral 15 mg or 30 mg upadacitinib daily. So, in the long run, all patients received upadacitinib in the second phase of the study but were blinded to the dose they were receiving. The results from the first 16 weeks of treatment were previously published. Simpson and colleagues reported on the results up to week 52 from the second phase of the study. They showed that at week 52, 82.0% and 79.1% of patients in Measure Up 1 and Measure Up 2 achieved a 75% improvement in EASI-75 when continuing on 15 mg upadacitinib and 84.9% and 84.3% in patients continuing 30 mg upadacitinib, respectively. More than 80% of patients who switched from placebo to upadacitinib at week 16 achieved EASI-75 at week 52. No safety signals were observed in this phase of the study that were not previously observed in other studies of upadacitinib for atopic dermatitis and other indications (rheumatoid arthritis and psoriatic arthritis). These results indicate that upadacitinib has durable efficacy with long-term treatment in moderate-to-severe AD. These studies are ongoing, and I look forward to future results reporting for even longer-term treatment.

It is an exciting time in dermatology with the arrival of multiple novel therapies for atopic dermatitis. The field has already benefited so much by the tremendous interest and research effort into understanding how to best manage this disease. With so many more treatments in the pipeline, perhaps the best is yet to come.

Dupilumab is a subcutaneous injection therapy that inhibits the interleukin 4 receptor alpha subunit. It has been approved in the United States for the treatment of adults with moderate-to-severe AD since 2017 and has since been approved for children and adolescents older than 6 years. Many real-world studies of the effectiveness of dupilumab have been published over the past few years. Kojanova and colleagues reported findings from a retrospective, multicenter study of 360 adults with severe AD who received dupilumab. They found that a high proportion of patients achieved a 75% improvement in the Eczema Area and Severity Index (EASI-75) at week 16 (66.6%), 1 year (89.5%), and 2 years (95.8%). Drug persistence rates were very high (> 90%) throughout the 2 years of therapy, suggesting that dupilumab was effective and well-tolerated.

Dupilumab was previously found to be associated with increased conjunctivitis in clinical trials and real-world studies. Schneeweiss and colleagues conducted a population-based longitudinal study of 5,004,117 patients with AD who newly initiated dupilumab, methotrexate, mycophenolate, and cyclosporine. They found that the risk of developing conjunctivitis diagnosed in clinical practice within 6 months of treatment initiation was approximately double with dupilumab compared with methotrexate, mycophenolate, or cyclosporine. Interestingly, comorbid asthma was found to be a risk factor for conjunctivitis in dupilumab initiators. This study provides insight into how commonly clinically significant conjunctivitis occurs with dupilumab treatment. Of note, the study results may underestimate the incidence of conjunctivitis because milder cases may go undetected.

Upadacitinib is an oral selective Janus kinase (JAK) 1 inhibitor that was approved in the United States in 2022 for the treatment of moderate-to-severe AD. Simpson and colleagues reported on the long-term efficacy and safety of oral upadacitinib from the phase 3 double-blind, randomized controlled trials Measure Up 1 and Measure Up 2 in adolescents and adults with moderate-to-severe atopic dermatitis ho had an inadequate response to topical therapy. The initial phase of the Measure Up 1 and Measure Up 2 studies was 16 weeks in duration, with a placebo control group. At week 16, patients who received 15 or 30 mg upadacitinib in the initial 16 weeks of the study continued to receive that dose. Patients who received placebo in the initial 16 weeks were randomly assigned to receive oral 15 mg or 30 mg upadacitinib daily. So, in the long run, all patients received upadacitinib in the second phase of the study but were blinded to the dose they were receiving. The results from the first 16 weeks of treatment were previously published. Simpson and colleagues reported on the results up to week 52 from the second phase of the study. They showed that at week 52, 82.0% and 79.1% of patients in Measure Up 1 and Measure Up 2 achieved a 75% improvement in EASI-75 when continuing on 15 mg upadacitinib and 84.9% and 84.3% in patients continuing 30 mg upadacitinib, respectively. More than 80% of patients who switched from placebo to upadacitinib at week 16 achieved EASI-75 at week 52. No safety signals were observed in this phase of the study that were not previously observed in other studies of upadacitinib for atopic dermatitis and other indications (rheumatoid arthritis and psoriatic arthritis). These results indicate that upadacitinib has durable efficacy with long-term treatment in moderate-to-severe AD. These studies are ongoing, and I look forward to future results reporting for even longer-term treatment.

It is an exciting time in dermatology with the arrival of multiple novel therapies for atopic dermatitis. The field has already benefited so much by the tremendous interest and research effort into understanding how to best manage this disease. With so many more treatments in the pipeline, perhaps the best is yet to come.

What prophylactic antibiotic should be administered intrapartum to a pregnant woman who is colonized with group B streptococci but who has a mild allergy to penicillin?

Continue to the answer...

In this situation, the drug of choice is intravenous cefazolin, 2 g initially then 1 g every 8 hours until delivery. For patients with a severe allergy to penicillin, the drugs of choice are either clindamycin, 900 mg intravenously every 8 hours (if sensitivity of the organism is confirmed), or vancomycin, 20 mg/kg intravenously every 8 hours (maximum of 2 g per single dose).

What prophylactic antibiotic should be administered intrapartum to a pregnant woman who is colonized with group B streptococci but who has a mild allergy to penicillin?

Continue to the answer...

In this situation, the drug of choice is intravenous cefazolin, 2 g initially then 1 g every 8 hours until delivery. For patients with a severe allergy to penicillin, the drugs of choice are either clindamycin, 900 mg intravenously every 8 hours (if sensitivity of the organism is confirmed), or vancomycin, 20 mg/kg intravenously every 8 hours (maximum of 2 g per single dose).

What prophylactic antibiotic should be administered intrapartum to a pregnant woman who is colonized with group B streptococci but who has a mild allergy to penicillin?

Continue to the answer...

In this situation, the drug of choice is intravenous cefazolin, 2 g initially then 1 g every 8 hours until delivery. For patients with a severe allergy to penicillin, the drugs of choice are either clindamycin, 900 mg intravenously every 8 hours (if sensitivity of the organism is confirmed), or vancomycin, 20 mg/kg intravenously every 8 hours (maximum of 2 g per single dose).

Ms. P, a 63-year-old woman with a history of schizophrenia whose symptoms have been stable on haloperidol 10 mg/d and ziprasidone 40 mg twice daily, presents to the outpatient clinic for a medication review. She mentions that she has noticed problems with her “memory.” She says she has had difficulty remembering names of people and places as well as difficulty concentrating while reading and writing, which she did months ago with ease. A Montreal Cognitive Assessment (MoCA) is conducted, and Ms. P scores 13/30, indicating moderate cognitive impairment. Visuospatial tasks and clock drawing are intact, but she exhibits impairments in working memory, attention, and concentration. One year ago, Ms. P’s MoCA score was 27/30. She agrees to a neurologic assessment and is referred to neurology for work-up.

Ms. P’s physical examination and routine laboratory tests are all within normal limits. The neurologic exam reveals deficits in working memory, concentration, and attention, but is otherwise unremarkable. MRI reveals mild chronic microvascular changes. The neurology service does not rule out cognitive impairment but recommends adjusting the dosage of Ms. P’s psychiatric medications to elucidate if her impairment of memory and attention is due to medications. However, Ms. P had been managed on her current regimen for several years and had not been hospitalized in many years. Previous attempts to taper her antipsychotics had resulted in worsening symptoms. Ms. P is reluctant to attempt a taper of her antipsychotics because she fears decompensation of her chronic illness. The treating team reviews Ms. P’s medication regimen, and notes that she is receiving benztropine 1 mg twice daily for prophylaxis of extrapyramidal symptoms (EPS). Ms. P denies past or present symptoms of drug-induced parkinsonism, dystonia, or akathisia as well as constipation, sialorrhea, blurry vision, palpitations, or urinary retention.

Benztropine is a tropane alkaloid that was synthetized by combining the tropine portion of atropine with the benzhydryl portion of diphenhydramine hydrochloride. It has anticholinergic and antihistaminic properties¹ and seems to inhibit the dopamine transporter. Benztropine is indicated for all forms of parkinsonism, including antipsychotic-induced parkinsonism, but is also prescribed for many off-label uses, including sialorrhea and akathisia (although many authors do not recommend anticholinergics for this purpose^2,3), and for prophylaxis of EPS. Benztropine can be administered intravenously, intramuscularly, or orally. Given orally, the typical dosing is twice daily with a maximum dose of 6 mg/d. Benztropine is preferred over diphenhydramine and trihexyphenidyl due to adverse effects of sedation or potential for misuse of the medication.¹

Second-generation antipsychotics (SGAs) have been associated with lower rates of neurologic adverse effects compared with first-generation antipsychotics (FGAs). Because SGAs are increasingly prescribed, the use of benztropine (along with other agents such as trihexyphenidyl) for EPS prophylaxis is not an evidence-based practice. However, despite a movement away from prophylactic management of movement disorders, benztropine continues to be prescribed for EPS and/or cholinergic symptoms, despite the peripheral and cognitive adverse effects of this agent and, in many instances, the lack of clear indication for its use.

According to the most recent edition of the American Psychiatric Association’s (APA) Practice Guideline for the Treatment of Patients with Schizophrenia,⁴ anticholinergics should only be used for preventing acute dystonia in conjunction with a long-acting injectable antipsychotic. Furthermore, the APA Guideline states anticholinergics may be used for drug-induced parkinsonism when the dose of an antipsychotic cannot be reduced and an alternative agent is required. However, the first-line agent for drug-induced parkinsonism is amantadine, and benztropine should only be considered if amantadine is contraindicated.⁴ The rationale for this guideline and for judicious use of anticholinergics is that like any pharmacologic treatment, anticholinergics (including benztropine) carry the potential for adverse effects. For benztropine, these range from mild effects such as tachycardia and constipation to paralytic ileus, increased falls, worsening of tardive dyskinesia (TD), and potential cognitive impairment. Literature suggests that the first step in managing cognitive concerns in a patient with schizophrenia should be a close review of medications, and avoidance of agents with anticholinergic properties.⁵

Prescribing benztropine for EPS

EPS, which include dystonia, akathisia, drug-induced parkinsonism, and TD, are very frequent adverse effects noted with antipsychotics. Benztropine has demonstrated benefit in managing acute dystonia and the APA Guideline recommends IM administration of either benztropine 1 mg or diphenhydramine 25 mg for this purpose.⁴ However, in our experience, the most frequent indication for long-term prescribing of benztropine is prophylaxis of antipsychoticinduced dystonia. This use was suggested by some older studies. In a 1987 study by Boyer et al,⁶ patients who were administered benztropine with haloperidol did not develop acute dystonia, while patients who received haloperidol alone developed dystonia. However, this was a small retrospective study with methodological issues. Boyer et al⁶ suggested discontinuing prophylaxis with benztropine within 1 week, as acute dystonia occurred within 2.5 days. Other researchers^7,8 have argued that short-term prophylaxis with benztropine for 1 week may work, especially during treatment with high-potency antipsychotics. However, in a review of the use of anticholinergics in conjunction with antipsychotics, Desmarais et al⁵ concluded that there is no need for prophylaxis and recommended alternative treatments. As we have noticed in Ms. P and other patients treated in our facilities, benztropine is frequently continued indefinitely without a clinical indication for its continuous use. Assessment and indication for continued use of benztropine should be considered regularly, and it should be discontinued when there is no clear indication for its use or when adverse effects emerge.

Prescribing benztropine for TD

TD is a subtype of tardive syndromes associated with the use of antipsychotics. It is characterized by repetitive involuntary movements such as lip smacking, puckering, chewing, or tongue protrusion. Proposed pathophysiological mechanisms include dopamine receptor hypersensitivity, N-methyl-D-aspartate (NMDA) receptor excitotoxicity, and gamma-aminobutyric acid (GABA)-containing neuron activity.

According to the APA Guideline, evidence of benztropine’s efficacy for the prevention of TD is lacking.⁴ A 2018 Cochrane systematic review⁹ was unable to provide a definitive conclusion regarding the effectiveness of benztropine and other anticholinergics for the treatment of antipsychotic-induced TD. While many clinicians believe that benztropine can be used to treat all types of EPS, there are no clear instances in reviewed literature where the efficacy of benztropine for treating TD could be reliably demonstrated. Furthermore, some literature suggests that anticholinergics such as benztropine increase the risk of developing TD.^5,10 The mechanism underlying benztropine’s ability to precipitate or exacerbate abnormal movements is unclear, though it is theorized that anticholinergic medications may inhibit dopamine reuptake into neurons, thus leading to an excess of dopamine in the synaptic cleft that manifests as dyskinesias.¹⁰ Some authors also recommend that the first step in the management of TD should be to gradually discontinue anticholinergics, as this has been associated with improvement in TD.¹¹

Continue to: Prescribing anticholinergics in specific patient populations...

In addition to the adverse effects described above, benztropine can affect cognition, as we observed in Ms. P. The cholinergic system plays a role in human cognition, and blockade of muscarinic receptors has been associated with impairments in working memory and prefrontal tasks.¹² These adverse cognitive effects are more pronounced in certain populations, including patients with schizophrenia and older adults.

Schizophrenia is associated with declining cognitive function, and the cognitive faculties of patients with schizophrenia may be worsened by anticholinergics. In patients with schizophrenia, social interactions and social integration are often impacted by profound negative symptoms such as social withdrawal and poverty of thought and speech.¹³ In a double-blind study by Baker et al,¹⁴ benztropine was found to have an impact on attention and concentration in patients with chronic schizophrenia. Baker et al¹⁴ found that patients with schizophrenia who were switched from benztropine to placebo increased their overall Wechsler Memory Scale scores compared to those maintained on benztropine. One crosssectional analysis found that a higher anticholinergic burden was associated with impairments across all cognitive domains, including memory, attention/control, executive and visuospatial functioning, and motor speed domains.¹⁵ Importantly, a higher anticholinergic medication burden was associated with worse cognitive performance.¹⁵ In addition to impairments in cognitive processing, anticholinergics have been associated with a decreased ability to benefit from psychosocial programs and impaired abilities to manage activities of daily living.⁴ In another study exploring the effects of discontinuing anticholinergics and the impact on movement disorders, Desmarais et al¹⁶ found patients experienced a significant improvement in scores on the Brief Assessment of Cognition in Schizophrenia after discontinuing anticholinergics. Vinogradov et al¹⁷ noted that “serum anticholinergic activity in schizophrenia patients shows a significant association with impaired performance in measures of verbal working memory and verbal learning memory and was significantly associated with a lowered response to an intensive course of computerized cognitive training.” They felt their findings underscored the cognitive cost of medications with high anticholinergic burden.

Geriatric patients. Careful consideration should be given before starting benztropine in patients age ≥65. The 2019 American Geriatric Society’s Beers Criteria¹⁸ recommend avoiding benztropine in geriatric patients; the level of recommendation is strong. Furthermore, the American Geriatric Society designates benztropine as a medication that should be avoided, and a nondrug approach or alternative medication be prescribed independent of the patient’s condition or diagnosis. In a recently published case report, Esang et al¹⁹ highlighted several salient findings from previous studies on the risks associated with anticholinergic use:

• any medications a patient takes with anticholinergic properties contribute to the overall anticholinergic load of a patient’s medication regimen
• the higher the anticholinergic burden, the greater the cognitive deficits
• switching from an FGA to an SGA may decrease the risk of EPS and may limit the need for anticholinergic medications such as benztropine for a particular patient.

One must also consider that the effects of multiple medications with anticholinergic properties is probably cumulative.

Alternatives for treating drug-induced parkinsonism

Antipsychotics exert their effects through antagonism of the D2 receptor, and this is the same mechanism that leads to parkinsonism. Specifically, the mechanism is believed to be D2 receptor antagonism in the striatum leading to disinhibition of striatal neurons containing GABA.¹¹ This disinhibition of medium spiny neurons is propagated when acetylcholine is released from cholinergic interneurons. Anticholinergics such as benztropine can remedy symptoms by blocking the signal of acetylcholine on the M1 receptors on medium spiny neurons. However, benztropine also has the propensity to decrease cholinergic transmission, thereby impairing storage of new information into long-term memory as well as impair perception of time—similar to effects seen with (for instance) diphenhydramine.²⁰

The first step in managing drug-induced parkinsonism is to monitor symptoms. The APA Guideline recommends monitoring for acute-onset EPS at weekly intervals when beginning treatment and until stable for 2 weeks, and then monitoring at every follow-up visit thereafter.⁴ The next recommendation for long-term management of drug-induced parkinsonism is reducing the antipsychotic dose, or replacing the patient’s antipsychotic with an antipsychotic that is less likely to precipitate parkinsonism,4 such as quetiapine, iloperidone, or clozapine.¹¹ If dose reduction is not possible, and the patient’s symptoms are severe, pharmacologic management is indicated. The APA Guideline recommends amantadine as a first-line agent because it is associated with fewer peripheral adverse effects and less impairment in cognition compared with benztropine.⁴ In a small (N = 60) doubleblind crossover trial, Gelenberg et al²⁰ found benztropine 4 mg/d—but not amantadine 200 mg/d—impaired free recall and perception of time, and participants’ perception of their own memory impairment was significantly greater with benztropine. Amantadine has also been compared to biperiden, a relatively selective M1 muscarinic receptor muscarinic agent. In a separate double-blind crossover study of 26 patients with chronic schizophrenia, Silver and Geraisy²¹ found that compared to amantadine, biperiden was associated with worse memory performance. The recommended starting dose of amantadine for parkinsonism is 100 mg in the morning, increased to 100 mg twice a day and titrated to a maximum daily dose of 300 mg/d in divided doses.⁴

Continue to: Alternatives for treating drug-induced akathisia...

Akathisia remains a relatively common adverse effect of SGAs, and the profound physical distress and impaired functioning caused by akathisia necessitates pharmacologic treatment. Despite frequent use in practice for presumed benefit in akathisia, benztropine is not effective for the treatment of akathisia and the APA Guideline recommends that long-term management should begin with an antipsychotic dose reduction, followed by a switch to an agent with less propensity to incite akathisia.⁴ Acute manifestations of akathisia must be treated, and mirtazapine, propranolol, or clonazepam may be considered as alternatives.⁴ Mirtazapine is dosed 7.5 mg to 10 mg nightly for akathisia, though it should be used in caution in patients at risk for mania.⁴ Mirtazapine’s potent 5-HT2A blockade at low doses may contribute to its utility in treating akathisia.² Propranolol, a nonselective lipophilic beta-adrenergic antagonist, also has demonstrated efficacy in managing akathisia, with recommended dosing of 40 mg to 80 mg twice daily.² Benzodiazepines such as clonazepam require judicious use for akathisia because they may also precipitate or exacerbate cognitive impairment.⁴

Alternatives for treating TD

As mentioned above, benztropine is not recommended for the treatment of TD.¹ The Box^4,22,23 outlines potential treatment options for TD.

Box

Discontinuing benztropine

Benztropine is recommended as a firstline agent for the management of acute dystonia, and it may be used temporarily for drug-induced parkinsonism, but it is not recommended to prevent EPS or TD. Given the multitude of adverse effects and cognitive impairment noted with anticholinergics, tapering should be considered for patients receiving an anticholinergic agent such as benztropine. Based on their review of earlier studies, Desmarais et al⁵ suggest a gradual 3-month discontinuation of benztropine. Multiple studies have demonstrated an ability to taper anticholinergics in days to months.⁴ However, gradual discontinuation is advisable to avoid cholinergic rebound and the reemergence of EPS, and to decrease the risk of neuroleptic malignant syndrome associated with sudden discontinuation.⁵ One suggested taper regimen is a decrease of 0.5 mg benztropine every week. Amantadine may be considered if parkinsonism is noted during the taper. Patients on benztropine may develop rebound symptoms, such as vivid dreams/nightmares; if this occurs, the taper rate can be slowed to a decrease of 0.5 mg every 2 weeks.⁴

Continue to: First do no harm...

Psychiatrists commonly prescribe benztropine to prevent EPS and TD, but available literature does not support the efficacy of benztropine for mitigating drug-induced parkinsonism, and studies report benztropine may significantly worsen cognitive processes and exacerbate TD.¹⁶ In addition, benztropine misuse has been correlated with euphoria and psychosis.¹⁶ More than 3 decades ago, the World Health Organization Heads of Centres Collaborating in WHO-Coordinated Studies on Biological Aspects of Mental Illness issued a consensus statement²⁴ discouraging the prophylactic use of anticholinergics for patients receiving antipsychotics, yet we still see patients on an indefinite regimen of benztropine.

As clinicians, our goals should be to optimize a patient’s functioning and quality of life, and to use the lowest dose of medication along with the fewest medications necessary to avoid adverse effects such as EPS. Benztropine is recommended as a first-line agent for the management of acute dystonia, but its continued or indefinite use to prevent antipsychotic-induced adverse effects is not recommended. While all pharmacologic interventions carry a risk of adverse effects, weighing the risk of those effects against the clinical benefits is the prerogative of a skilled clinician. Benztropine and other anticholinergics prescribed for prophylactic purposes have numerous adverse effects, limited clinical utility, and a deleterious effect on quality of life. Furthermore, benztropine prophylaxis of drug-induced parkinsonism does not seem to be warranted, and the risks do not seem to outweigh the harm benztropine may cause, with the possible exception of “prophylactic” treatment of dystonia that is discontinued in a few days, as some researchers have suggested.^6-8 The preventive value of benztropine has not been demonstrated. It is time we took inventory of medications that might cause more harm than good, rely on current treatment guidelines instead of habit, and use these agents judiciously while considering replacement with novel, safer medications whenever possible.

CASE CONTINUED

The clinical team considers benztropine’s ability to cause cognitive effects, and decides to taper and discontinue it over 1 month. Ms. P is seen in an outpatient clinic within 1 month of discontinuing benztropine. She reports that her difficulty remembering words and details has improved. She also says that she is now able to concentrate on writing and reading. The consulting neurologist also notes improvement. Ms. P continues to report improvement in symptoms over the next 2 months of follow-up, and says that her mood improved and she has less apathy.

Bottom Line

Benztropine is a first-line medication for acute dystonia, but its continued or indefinite use for preventing antipsychotic-induced adverse effects is not recommended. Given the multitude of adverse effects and cognitive impairment noted with anticholinergics, tapering should be considered for patients receiving an anticholinergic medication such as benztropine.

Ms. P, a 63-year-old woman with a history of schizophrenia whose symptoms have been stable on haloperidol 10 mg/d and ziprasidone 40 mg twice daily, presents to the outpatient clinic for a medication review. She mentions that she has noticed problems with her “memory.” She says she has had difficulty remembering names of people and places as well as difficulty concentrating while reading and writing, which she did months ago with ease. A Montreal Cognitive Assessment (MoCA) is conducted, and Ms. P scores 13/30, indicating moderate cognitive impairment. Visuospatial tasks and clock drawing are intact, but she exhibits impairments in working memory, attention, and concentration. One year ago, Ms. P’s MoCA score was 27/30. She agrees to a neurologic assessment and is referred to neurology for work-up.

Ms. P’s physical examination and routine laboratory tests are all within normal limits. The neurologic exam reveals deficits in working memory, concentration, and attention, but is otherwise unremarkable. MRI reveals mild chronic microvascular changes. The neurology service does not rule out cognitive impairment but recommends adjusting the dosage of Ms. P’s psychiatric medications to elucidate if her impairment of memory and attention is due to medications. However, Ms. P had been managed on her current regimen for several years and had not been hospitalized in many years. Previous attempts to taper her antipsychotics had resulted in worsening symptoms. Ms. P is reluctant to attempt a taper of her antipsychotics because she fears decompensation of her chronic illness. The treating team reviews Ms. P’s medication regimen, and notes that she is receiving benztropine 1 mg twice daily for prophylaxis of extrapyramidal symptoms (EPS). Ms. P denies past or present symptoms of drug-induced parkinsonism, dystonia, or akathisia as well as constipation, sialorrhea, blurry vision, palpitations, or urinary retention.

Benztropine is a tropane alkaloid that was synthetized by combining the tropine portion of atropine with the benzhydryl portion of diphenhydramine hydrochloride. It has anticholinergic and antihistaminic properties¹ and seems to inhibit the dopamine transporter. Benztropine is indicated for all forms of parkinsonism, including antipsychotic-induced parkinsonism, but is also prescribed for many off-label uses, including sialorrhea and akathisia (although many authors do not recommend anticholinergics for this purpose^2,3), and for prophylaxis of EPS. Benztropine can be administered intravenously, intramuscularly, or orally. Given orally, the typical dosing is twice daily with a maximum dose of 6 mg/d. Benztropine is preferred over diphenhydramine and trihexyphenidyl due to adverse effects of sedation or potential for misuse of the medication.¹

Second-generation antipsychotics (SGAs) have been associated with lower rates of neurologic adverse effects compared with first-generation antipsychotics (FGAs). Because SGAs are increasingly prescribed, the use of benztropine (along with other agents such as trihexyphenidyl) for EPS prophylaxis is not an evidence-based practice. However, despite a movement away from prophylactic management of movement disorders, benztropine continues to be prescribed for EPS and/or cholinergic symptoms, despite the peripheral and cognitive adverse effects of this agent and, in many instances, the lack of clear indication for its use.

According to the most recent edition of the American Psychiatric Association’s (APA) Practice Guideline for the Treatment of Patients with Schizophrenia,⁴ anticholinergics should only be used for preventing acute dystonia in conjunction with a long-acting injectable antipsychotic. Furthermore, the APA Guideline states anticholinergics may be used for drug-induced parkinsonism when the dose of an antipsychotic cannot be reduced and an alternative agent is required. However, the first-line agent for drug-induced parkinsonism is amantadine, and benztropine should only be considered if amantadine is contraindicated.⁴ The rationale for this guideline and for judicious use of anticholinergics is that like any pharmacologic treatment, anticholinergics (including benztropine) carry the potential for adverse effects. For benztropine, these range from mild effects such as tachycardia and constipation to paralytic ileus, increased falls, worsening of tardive dyskinesia (TD), and potential cognitive impairment. Literature suggests that the first step in managing cognitive concerns in a patient with schizophrenia should be a close review of medications, and avoidance of agents with anticholinergic properties.⁵

Prescribing benztropine for EPS

EPS, which include dystonia, akathisia, drug-induced parkinsonism, and TD, are very frequent adverse effects noted with antipsychotics. Benztropine has demonstrated benefit in managing acute dystonia and the APA Guideline recommends IM administration of either benztropine 1 mg or diphenhydramine 25 mg for this purpose.⁴ However, in our experience, the most frequent indication for long-term prescribing of benztropine is prophylaxis of antipsychoticinduced dystonia. This use was suggested by some older studies. In a 1987 study by Boyer et al,⁶ patients who were administered benztropine with haloperidol did not develop acute dystonia, while patients who received haloperidol alone developed dystonia. However, this was a small retrospective study with methodological issues. Boyer et al⁶ suggested discontinuing prophylaxis with benztropine within 1 week, as acute dystonia occurred within 2.5 days. Other researchers^7,8 have argued that short-term prophylaxis with benztropine for 1 week may work, especially during treatment with high-potency antipsychotics. However, in a review of the use of anticholinergics in conjunction with antipsychotics, Desmarais et al⁵ concluded that there is no need for prophylaxis and recommended alternative treatments. As we have noticed in Ms. P and other patients treated in our facilities, benztropine is frequently continued indefinitely without a clinical indication for its continuous use. Assessment and indication for continued use of benztropine should be considered regularly, and it should be discontinued when there is no clear indication for its use or when adverse effects emerge.

Prescribing benztropine for TD

TD is a subtype of tardive syndromes associated with the use of antipsychotics. It is characterized by repetitive involuntary movements such as lip smacking, puckering, chewing, or tongue protrusion. Proposed pathophysiological mechanisms include dopamine receptor hypersensitivity, N-methyl-D-aspartate (NMDA) receptor excitotoxicity, and gamma-aminobutyric acid (GABA)-containing neuron activity.

According to the APA Guideline, evidence of benztropine’s efficacy for the prevention of TD is lacking.⁴ A 2018 Cochrane systematic review⁹ was unable to provide a definitive conclusion regarding the effectiveness of benztropine and other anticholinergics for the treatment of antipsychotic-induced TD. While many clinicians believe that benztropine can be used to treat all types of EPS, there are no clear instances in reviewed literature where the efficacy of benztropine for treating TD could be reliably demonstrated. Furthermore, some literature suggests that anticholinergics such as benztropine increase the risk of developing TD.^5,10 The mechanism underlying benztropine’s ability to precipitate or exacerbate abnormal movements is unclear, though it is theorized that anticholinergic medications may inhibit dopamine reuptake into neurons, thus leading to an excess of dopamine in the synaptic cleft that manifests as dyskinesias.¹⁰ Some authors also recommend that the first step in the management of TD should be to gradually discontinue anticholinergics, as this has been associated with improvement in TD.¹¹

Continue to: Prescribing anticholinergics in specific patient populations...

In addition to the adverse effects described above, benztropine can affect cognition, as we observed in Ms. P. The cholinergic system plays a role in human cognition, and blockade of muscarinic receptors has been associated with impairments in working memory and prefrontal tasks.¹² These adverse cognitive effects are more pronounced in certain populations, including patients with schizophrenia and older adults.

Schizophrenia is associated with declining cognitive function, and the cognitive faculties of patients with schizophrenia may be worsened by anticholinergics. In patients with schizophrenia, social interactions and social integration are often impacted by profound negative symptoms such as social withdrawal and poverty of thought and speech.¹³ In a double-blind study by Baker et al,¹⁴ benztropine was found to have an impact on attention and concentration in patients with chronic schizophrenia. Baker et al¹⁴ found that patients with schizophrenia who were switched from benztropine to placebo increased their overall Wechsler Memory Scale scores compared to those maintained on benztropine. One crosssectional analysis found that a higher anticholinergic burden was associated with impairments across all cognitive domains, including memory, attention/control, executive and visuospatial functioning, and motor speed domains.¹⁵ Importantly, a higher anticholinergic medication burden was associated with worse cognitive performance.¹⁵ In addition to impairments in cognitive processing, anticholinergics have been associated with a decreased ability to benefit from psychosocial programs and impaired abilities to manage activities of daily living.⁴ In another study exploring the effects of discontinuing anticholinergics and the impact on movement disorders, Desmarais et al¹⁶ found patients experienced a significant improvement in scores on the Brief Assessment of Cognition in Schizophrenia after discontinuing anticholinergics. Vinogradov et al¹⁷ noted that “serum anticholinergic activity in schizophrenia patients shows a significant association with impaired performance in measures of verbal working memory and verbal learning memory and was significantly associated with a lowered response to an intensive course of computerized cognitive training.” They felt their findings underscored the cognitive cost of medications with high anticholinergic burden.

Geriatric patients. Careful consideration should be given before starting benztropine in patients age ≥65. The 2019 American Geriatric Society’s Beers Criteria¹⁸ recommend avoiding benztropine in geriatric patients; the level of recommendation is strong. Furthermore, the American Geriatric Society designates benztropine as a medication that should be avoided, and a nondrug approach or alternative medication be prescribed independent of the patient’s condition or diagnosis. In a recently published case report, Esang et al¹⁹ highlighted several salient findings from previous studies on the risks associated with anticholinergic use:

• any medications a patient takes with anticholinergic properties contribute to the overall anticholinergic load of a patient’s medication regimen
• the higher the anticholinergic burden, the greater the cognitive deficits
• switching from an FGA to an SGA may decrease the risk of EPS and may limit the need for anticholinergic medications such as benztropine for a particular patient.

One must also consider that the effects of multiple medications with anticholinergic properties is probably cumulative.

Alternatives for treating drug-induced parkinsonism

Antipsychotics exert their effects through antagonism of the D2 receptor, and this is the same mechanism that leads to parkinsonism. Specifically, the mechanism is believed to be D2 receptor antagonism in the striatum leading to disinhibition of striatal neurons containing GABA.¹¹ This disinhibition of medium spiny neurons is propagated when acetylcholine is released from cholinergic interneurons. Anticholinergics such as benztropine can remedy symptoms by blocking the signal of acetylcholine on the M1 receptors on medium spiny neurons. However, benztropine also has the propensity to decrease cholinergic transmission, thereby impairing storage of new information into long-term memory as well as impair perception of time—similar to effects seen with (for instance) diphenhydramine.²⁰

The first step in managing drug-induced parkinsonism is to monitor symptoms. The APA Guideline recommends monitoring for acute-onset EPS at weekly intervals when beginning treatment and until stable for 2 weeks, and then monitoring at every follow-up visit thereafter.⁴ The next recommendation for long-term management of drug-induced parkinsonism is reducing the antipsychotic dose, or replacing the patient’s antipsychotic with an antipsychotic that is less likely to precipitate parkinsonism,4 such as quetiapine, iloperidone, or clozapine.¹¹ If dose reduction is not possible, and the patient’s symptoms are severe, pharmacologic management is indicated. The APA Guideline recommends amantadine as a first-line agent because it is associated with fewer peripheral adverse effects and less impairment in cognition compared with benztropine.⁴ In a small (N = 60) doubleblind crossover trial, Gelenberg et al²⁰ found benztropine 4 mg/d—but not amantadine 200 mg/d—impaired free recall and perception of time, and participants’ perception of their own memory impairment was significantly greater with benztropine. Amantadine has also been compared to biperiden, a relatively selective M1 muscarinic receptor muscarinic agent. In a separate double-blind crossover study of 26 patients with chronic schizophrenia, Silver and Geraisy²¹ found that compared to amantadine, biperiden was associated with worse memory performance. The recommended starting dose of amantadine for parkinsonism is 100 mg in the morning, increased to 100 mg twice a day and titrated to a maximum daily dose of 300 mg/d in divided doses.⁴

Continue to: Alternatives for treating drug-induced akathisia...

Akathisia remains a relatively common adverse effect of SGAs, and the profound physical distress and impaired functioning caused by akathisia necessitates pharmacologic treatment. Despite frequent use in practice for presumed benefit in akathisia, benztropine is not effective for the treatment of akathisia and the APA Guideline recommends that long-term management should begin with an antipsychotic dose reduction, followed by a switch to an agent with less propensity to incite akathisia.⁴ Acute manifestations of akathisia must be treated, and mirtazapine, propranolol, or clonazepam may be considered as alternatives.⁴ Mirtazapine is dosed 7.5 mg to 10 mg nightly for akathisia, though it should be used in caution in patients at risk for mania.⁴ Mirtazapine’s potent 5-HT2A blockade at low doses may contribute to its utility in treating akathisia.² Propranolol, a nonselective lipophilic beta-adrenergic antagonist, also has demonstrated efficacy in managing akathisia, with recommended dosing of 40 mg to 80 mg twice daily.² Benzodiazepines such as clonazepam require judicious use for akathisia because they may also precipitate or exacerbate cognitive impairment.⁴

Alternatives for treating TD

As mentioned above, benztropine is not recommended for the treatment of TD.¹ The Box^4,22,23 outlines potential treatment options for TD.

Box

Discontinuing benztropine

Benztropine is recommended as a firstline agent for the management of acute dystonia, and it may be used temporarily for drug-induced parkinsonism, but it is not recommended to prevent EPS or TD. Given the multitude of adverse effects and cognitive impairment noted with anticholinergics, tapering should be considered for patients receiving an anticholinergic agent such as benztropine. Based on their review of earlier studies, Desmarais et al⁵ suggest a gradual 3-month discontinuation of benztropine. Multiple studies have demonstrated an ability to taper anticholinergics in days to months.⁴ However, gradual discontinuation is advisable to avoid cholinergic rebound and the reemergence of EPS, and to decrease the risk of neuroleptic malignant syndrome associated with sudden discontinuation.⁵ One suggested taper regimen is a decrease of 0.5 mg benztropine every week. Amantadine may be considered if parkinsonism is noted during the taper. Patients on benztropine may develop rebound symptoms, such as vivid dreams/nightmares; if this occurs, the taper rate can be slowed to a decrease of 0.5 mg every 2 weeks.⁴

Continue to: First do no harm...

Psychiatrists commonly prescribe benztropine to prevent EPS and TD, but available literature does not support the efficacy of benztropine for mitigating drug-induced parkinsonism, and studies report benztropine may significantly worsen cognitive processes and exacerbate TD.¹⁶ In addition, benztropine misuse has been correlated with euphoria and psychosis.¹⁶ More than 3 decades ago, the World Health Organization Heads of Centres Collaborating in WHO-Coordinated Studies on Biological Aspects of Mental Illness issued a consensus statement²⁴ discouraging the prophylactic use of anticholinergics for patients receiving antipsychotics, yet we still see patients on an indefinite regimen of benztropine.

As clinicians, our goals should be to optimize a patient’s functioning and quality of life, and to use the lowest dose of medication along with the fewest medications necessary to avoid adverse effects such as EPS. Benztropine is recommended as a first-line agent for the management of acute dystonia, but its continued or indefinite use to prevent antipsychotic-induced adverse effects is not recommended. While all pharmacologic interventions carry a risk of adverse effects, weighing the risk of those effects against the clinical benefits is the prerogative of a skilled clinician. Benztropine and other anticholinergics prescribed for prophylactic purposes have numerous adverse effects, limited clinical utility, and a deleterious effect on quality of life. Furthermore, benztropine prophylaxis of drug-induced parkinsonism does not seem to be warranted, and the risks do not seem to outweigh the harm benztropine may cause, with the possible exception of “prophylactic” treatment of dystonia that is discontinued in a few days, as some researchers have suggested.^6-8 The preventive value of benztropine has not been demonstrated. It is time we took inventory of medications that might cause more harm than good, rely on current treatment guidelines instead of habit, and use these agents judiciously while considering replacement with novel, safer medications whenever possible.

CASE CONTINUED

The clinical team considers benztropine’s ability to cause cognitive effects, and decides to taper and discontinue it over 1 month. Ms. P is seen in an outpatient clinic within 1 month of discontinuing benztropine. She reports that her difficulty remembering words and details has improved. She also says that she is now able to concentrate on writing and reading. The consulting neurologist also notes improvement. Ms. P continues to report improvement in symptoms over the next 2 months of follow-up, and says that her mood improved and she has less apathy.

Bottom Line

Benztropine is a first-line medication for acute dystonia, but its continued or indefinite use for preventing antipsychotic-induced adverse effects is not recommended. Given the multitude of adverse effects and cognitive impairment noted with anticholinergics, tapering should be considered for patients receiving an anticholinergic medication such as benztropine.

Ms. P, a 63-year-old woman with a history of schizophrenia whose symptoms have been stable on haloperidol 10 mg/d and ziprasidone 40 mg twice daily, presents to the outpatient clinic for a medication review. She mentions that she has noticed problems with her “memory.” She says she has had difficulty remembering names of people and places as well as difficulty concentrating while reading and writing, which she did months ago with ease. A Montreal Cognitive Assessment (MoCA) is conducted, and Ms. P scores 13/30, indicating moderate cognitive impairment. Visuospatial tasks and clock drawing are intact, but she exhibits impairments in working memory, attention, and concentration. One year ago, Ms. P’s MoCA score was 27/30. She agrees to a neurologic assessment and is referred to neurology for work-up.

Ms. P’s physical examination and routine laboratory tests are all within normal limits. The neurologic exam reveals deficits in working memory, concentration, and attention, but is otherwise unremarkable. MRI reveals mild chronic microvascular changes. The neurology service does not rule out cognitive impairment but recommends adjusting the dosage of Ms. P’s psychiatric medications to elucidate if her impairment of memory and attention is due to medications. However, Ms. P had been managed on her current regimen for several years and had not been hospitalized in many years. Previous attempts to taper her antipsychotics had resulted in worsening symptoms. Ms. P is reluctant to attempt a taper of her antipsychotics because she fears decompensation of her chronic illness. The treating team reviews Ms. P’s medication regimen, and notes that she is receiving benztropine 1 mg twice daily for prophylaxis of extrapyramidal symptoms (EPS). Ms. P denies past or present symptoms of drug-induced parkinsonism, dystonia, or akathisia as well as constipation, sialorrhea, blurry vision, palpitations, or urinary retention.

Benztropine is a tropane alkaloid that was synthetized by combining the tropine portion of atropine with the benzhydryl portion of diphenhydramine hydrochloride. It has anticholinergic and antihistaminic properties¹ and seems to inhibit the dopamine transporter. Benztropine is indicated for all forms of parkinsonism, including antipsychotic-induced parkinsonism, but is also prescribed for many off-label uses, including sialorrhea and akathisia (although many authors do not recommend anticholinergics for this purpose^2,3), and for prophylaxis of EPS. Benztropine can be administered intravenously, intramuscularly, or orally. Given orally, the typical dosing is twice daily with a maximum dose of 6 mg/d. Benztropine is preferred over diphenhydramine and trihexyphenidyl due to adverse effects of sedation or potential for misuse of the medication.¹

Second-generation antipsychotics (SGAs) have been associated with lower rates of neurologic adverse effects compared with first-generation antipsychotics (FGAs). Because SGAs are increasingly prescribed, the use of benztropine (along with other agents such as trihexyphenidyl) for EPS prophylaxis is not an evidence-based practice. However, despite a movement away from prophylactic management of movement disorders, benztropine continues to be prescribed for EPS and/or cholinergic symptoms, despite the peripheral and cognitive adverse effects of this agent and, in many instances, the lack of clear indication for its use.

According to the most recent edition of the American Psychiatric Association’s (APA) Practice Guideline for the Treatment of Patients with Schizophrenia,⁴ anticholinergics should only be used for preventing acute dystonia in conjunction with a long-acting injectable antipsychotic. Furthermore, the APA Guideline states anticholinergics may be used for drug-induced parkinsonism when the dose of an antipsychotic cannot be reduced and an alternative agent is required. However, the first-line agent for drug-induced parkinsonism is amantadine, and benztropine should only be considered if amantadine is contraindicated.⁴ The rationale for this guideline and for judicious use of anticholinergics is that like any pharmacologic treatment, anticholinergics (including benztropine) carry the potential for adverse effects. For benztropine, these range from mild effects such as tachycardia and constipation to paralytic ileus, increased falls, worsening of tardive dyskinesia (TD), and potential cognitive impairment. Literature suggests that the first step in managing cognitive concerns in a patient with schizophrenia should be a close review of medications, and avoidance of agents with anticholinergic properties.⁵

Prescribing benztropine for EPS

EPS, which include dystonia, akathisia, drug-induced parkinsonism, and TD, are very frequent adverse effects noted with antipsychotics. Benztropine has demonstrated benefit in managing acute dystonia and the APA Guideline recommends IM administration of either benztropine 1 mg or diphenhydramine 25 mg for this purpose.⁴ However, in our experience, the most frequent indication for long-term prescribing of benztropine is prophylaxis of antipsychoticinduced dystonia. This use was suggested by some older studies. In a 1987 study by Boyer et al,⁶ patients who were administered benztropine with haloperidol did not develop acute dystonia, while patients who received haloperidol alone developed dystonia. However, this was a small retrospective study with methodological issues. Boyer et al⁶ suggested discontinuing prophylaxis with benztropine within 1 week, as acute dystonia occurred within 2.5 days. Other researchers^7,8 have argued that short-term prophylaxis with benztropine for 1 week may work, especially during treatment with high-potency antipsychotics. However, in a review of the use of anticholinergics in conjunction with antipsychotics, Desmarais et al⁵ concluded that there is no need for prophylaxis and recommended alternative treatments. As we have noticed in Ms. P and other patients treated in our facilities, benztropine is frequently continued indefinitely without a clinical indication for its continuous use. Assessment and indication for continued use of benztropine should be considered regularly, and it should be discontinued when there is no clear indication for its use or when adverse effects emerge.

Prescribing benztropine for TD

TD is a subtype of tardive syndromes associated with the use of antipsychotics. It is characterized by repetitive involuntary movements such as lip smacking, puckering, chewing, or tongue protrusion. Proposed pathophysiological mechanisms include dopamine receptor hypersensitivity, N-methyl-D-aspartate (NMDA) receptor excitotoxicity, and gamma-aminobutyric acid (GABA)-containing neuron activity.

According to the APA Guideline, evidence of benztropine’s efficacy for the prevention of TD is lacking.⁴ A 2018 Cochrane systematic review⁹ was unable to provide a definitive conclusion regarding the effectiveness of benztropine and other anticholinergics for the treatment of antipsychotic-induced TD. While many clinicians believe that benztropine can be used to treat all types of EPS, there are no clear instances in reviewed literature where the efficacy of benztropine for treating TD could be reliably demonstrated. Furthermore, some literature suggests that anticholinergics such as benztropine increase the risk of developing TD.^5,10 The mechanism underlying benztropine’s ability to precipitate or exacerbate abnormal movements is unclear, though it is theorized that anticholinergic medications may inhibit dopamine reuptake into neurons, thus leading to an excess of dopamine in the synaptic cleft that manifests as dyskinesias.¹⁰ Some authors also recommend that the first step in the management of TD should be to gradually discontinue anticholinergics, as this has been associated with improvement in TD.¹¹

Continue to: Prescribing anticholinergics in specific patient populations...

In addition to the adverse effects described above, benztropine can affect cognition, as we observed in Ms. P. The cholinergic system plays a role in human cognition, and blockade of muscarinic receptors has been associated with impairments in working memory and prefrontal tasks.¹² These adverse cognitive effects are more pronounced in certain populations, including patients with schizophrenia and older adults.

Schizophrenia is associated with declining cognitive function, and the cognitive faculties of patients with schizophrenia may be worsened by anticholinergics. In patients with schizophrenia, social interactions and social integration are often impacted by profound negative symptoms such as social withdrawal and poverty of thought and speech.¹³ In a double-blind study by Baker et al,¹⁴ benztropine was found to have an impact on attention and concentration in patients with chronic schizophrenia. Baker et al¹⁴ found that patients with schizophrenia who were switched from benztropine to placebo increased their overall Wechsler Memory Scale scores compared to those maintained on benztropine. One crosssectional analysis found that a higher anticholinergic burden was associated with impairments across all cognitive domains, including memory, attention/control, executive and visuospatial functioning, and motor speed domains.¹⁵ Importantly, a higher anticholinergic medication burden was associated with worse cognitive performance.¹⁵ In addition to impairments in cognitive processing, anticholinergics have been associated with a decreased ability to benefit from psychosocial programs and impaired abilities to manage activities of daily living.⁴ In another study exploring the effects of discontinuing anticholinergics and the impact on movement disorders, Desmarais et al¹⁶ found patients experienced a significant improvement in scores on the Brief Assessment of Cognition in Schizophrenia after discontinuing anticholinergics. Vinogradov et al¹⁷ noted that “serum anticholinergic activity in schizophrenia patients shows a significant association with impaired performance in measures of verbal working memory and verbal learning memory and was significantly associated with a lowered response to an intensive course of computerized cognitive training.” They felt their findings underscored the cognitive cost of medications with high anticholinergic burden.

Geriatric patients. Careful consideration should be given before starting benztropine in patients age ≥65. The 2019 American Geriatric Society’s Beers Criteria¹⁸ recommend avoiding benztropine in geriatric patients; the level of recommendation is strong. Furthermore, the American Geriatric Society designates benztropine as a medication that should be avoided, and a nondrug approach or alternative medication be prescribed independent of the patient’s condition or diagnosis. In a recently published case report, Esang et al¹⁹ highlighted several salient findings from previous studies on the risks associated with anticholinergic use:

• any medications a patient takes with anticholinergic properties contribute to the overall anticholinergic load of a patient’s medication regimen
• the higher the anticholinergic burden, the greater the cognitive deficits
• switching from an FGA to an SGA may decrease the risk of EPS and may limit the need for anticholinergic medications such as benztropine for a particular patient.

One must also consider that the effects of multiple medications with anticholinergic properties is probably cumulative.

Alternatives for treating drug-induced parkinsonism

Antipsychotics exert their effects through antagonism of the D2 receptor, and this is the same mechanism that leads to parkinsonism. Specifically, the mechanism is believed to be D2 receptor antagonism in the striatum leading to disinhibition of striatal neurons containing GABA.¹¹ This disinhibition of medium spiny neurons is propagated when acetylcholine is released from cholinergic interneurons. Anticholinergics such as benztropine can remedy symptoms by blocking the signal of acetylcholine on the M1 receptors on medium spiny neurons. However, benztropine also has the propensity to decrease cholinergic transmission, thereby impairing storage of new information into long-term memory as well as impair perception of time—similar to effects seen with (for instance) diphenhydramine.²⁰

The first step in managing drug-induced parkinsonism is to monitor symptoms. The APA Guideline recommends monitoring for acute-onset EPS at weekly intervals when beginning treatment and until stable for 2 weeks, and then monitoring at every follow-up visit thereafter.⁴ The next recommendation for long-term management of drug-induced parkinsonism is reducing the antipsychotic dose, or replacing the patient’s antipsychotic with an antipsychotic that is less likely to precipitate parkinsonism,4 such as quetiapine, iloperidone, or clozapine.¹¹ If dose reduction is not possible, and the patient’s symptoms are severe, pharmacologic management is indicated. The APA Guideline recommends amantadine as a first-line agent because it is associated with fewer peripheral adverse effects and less impairment in cognition compared with benztropine.⁴ In a small (N = 60) doubleblind crossover trial, Gelenberg et al²⁰ found benztropine 4 mg/d—but not amantadine 200 mg/d—impaired free recall and perception of time, and participants’ perception of their own memory impairment was significantly greater with benztropine. Amantadine has also been compared to biperiden, a relatively selective M1 muscarinic receptor muscarinic agent. In a separate double-blind crossover study of 26 patients with chronic schizophrenia, Silver and Geraisy²¹ found that compared to amantadine, biperiden was associated with worse memory performance. The recommended starting dose of amantadine for parkinsonism is 100 mg in the morning, increased to 100 mg twice a day and titrated to a maximum daily dose of 300 mg/d in divided doses.⁴

Continue to: Alternatives for treating drug-induced akathisia...

Akathisia remains a relatively common adverse effect of SGAs, and the profound physical distress and impaired functioning caused by akathisia necessitates pharmacologic treatment. Despite frequent use in practice for presumed benefit in akathisia, benztropine is not effective for the treatment of akathisia and the APA Guideline recommends that long-term management should begin with an antipsychotic dose reduction, followed by a switch to an agent with less propensity to incite akathisia.⁴ Acute manifestations of akathisia must be treated, and mirtazapine, propranolol, or clonazepam may be considered as alternatives.⁴ Mirtazapine is dosed 7.5 mg to 10 mg nightly for akathisia, though it should be used in caution in patients at risk for mania.⁴ Mirtazapine’s potent 5-HT2A blockade at low doses may contribute to its utility in treating akathisia.² Propranolol, a nonselective lipophilic beta-adrenergic antagonist, also has demonstrated efficacy in managing akathisia, with recommended dosing of 40 mg to 80 mg twice daily.² Benzodiazepines such as clonazepam require judicious use for akathisia because they may also precipitate or exacerbate cognitive impairment.⁴

Alternatives for treating TD

As mentioned above, benztropine is not recommended for the treatment of TD.¹ The Box^4,22,23 outlines potential treatment options for TD.

Box

Discontinuing benztropine

Benztropine is recommended as a firstline agent for the management of acute dystonia, and it may be used temporarily for drug-induced parkinsonism, but it is not recommended to prevent EPS or TD. Given the multitude of adverse effects and cognitive impairment noted with anticholinergics, tapering should be considered for patients receiving an anticholinergic agent such as benztropine. Based on their review of earlier studies, Desmarais et al⁵ suggest a gradual 3-month discontinuation of benztropine. Multiple studies have demonstrated an ability to taper anticholinergics in days to months.⁴ However, gradual discontinuation is advisable to avoid cholinergic rebound and the reemergence of EPS, and to decrease the risk of neuroleptic malignant syndrome associated with sudden discontinuation.⁵ One suggested taper regimen is a decrease of 0.5 mg benztropine every week. Amantadine may be considered if parkinsonism is noted during the taper. Patients on benztropine may develop rebound symptoms, such as vivid dreams/nightmares; if this occurs, the taper rate can be slowed to a decrease of 0.5 mg every 2 weeks.⁴

Continue to: First do no harm...

Psychiatrists commonly prescribe benztropine to prevent EPS and TD, but available literature does not support the efficacy of benztropine for mitigating drug-induced parkinsonism, and studies report benztropine may significantly worsen cognitive processes and exacerbate TD.¹⁶ In addition, benztropine misuse has been correlated with euphoria and psychosis.¹⁶ More than 3 decades ago, the World Health Organization Heads of Centres Collaborating in WHO-Coordinated Studies on Biological Aspects of Mental Illness issued a consensus statement²⁴ discouraging the prophylactic use of anticholinergics for patients receiving antipsychotics, yet we still see patients on an indefinite regimen of benztropine.

As clinicians, our goals should be to optimize a patient’s functioning and quality of life, and to use the lowest dose of medication along with the fewest medications necessary to avoid adverse effects such as EPS. Benztropine is recommended as a first-line agent for the management of acute dystonia, but its continued or indefinite use to prevent antipsychotic-induced adverse effects is not recommended. While all pharmacologic interventions carry a risk of adverse effects, weighing the risk of those effects against the clinical benefits is the prerogative of a skilled clinician. Benztropine and other anticholinergics prescribed for prophylactic purposes have numerous adverse effects, limited clinical utility, and a deleterious effect on quality of life. Furthermore, benztropine prophylaxis of drug-induced parkinsonism does not seem to be warranted, and the risks do not seem to outweigh the harm benztropine may cause, with the possible exception of “prophylactic” treatment of dystonia that is discontinued in a few days, as some researchers have suggested.^6-8 The preventive value of benztropine has not been demonstrated. It is time we took inventory of medications that might cause more harm than good, rely on current treatment guidelines instead of habit, and use these agents judiciously while considering replacement with novel, safer medications whenever possible.

CASE CONTINUED

The clinical team considers benztropine’s ability to cause cognitive effects, and decides to taper and discontinue it over 1 month. Ms. P is seen in an outpatient clinic within 1 month of discontinuing benztropine. She reports that her difficulty remembering words and details has improved. She also says that she is now able to concentrate on writing and reading. The consulting neurologist also notes improvement. Ms. P continues to report improvement in symptoms over the next 2 months of follow-up, and says that her mood improved and she has less apathy.

Bottom Line

Benztropine is a first-line medication for acute dystonia, but its continued or indefinite use for preventing antipsychotic-induced adverse effects is not recommended. Given the multitude of adverse effects and cognitive impairment noted with anticholinergics, tapering should be considered for patients receiving an anticholinergic medication such as benztropine.

SECOND OF 2 PARTS

Evidence supports the crucial role of early intervention and nonpharmacologic approaches

A large percentage of individuals with autism spectrum disorder (ASD) experience persisting significant social deficits in adulthood,¹ which often leads to isolation, depressive symptoms, and poor occupational and relationship functioning.^2,3 Childhood is a vital time for making the most significant and lasting changes that can improve functioning of individuals with ASD. Psychiatrists and other physicians who treat children are in a key role to influence outcomes of children at risk for or diagnosed with ASD.

This article provides updates on various aspects of ASD diagnosis and treatment (based on available evidence up to March 2020). Part 1 (Current Psychiatry, March 2022) focused on early detection and diagnosis. Here in Part 2, I describe an overview of treatment strategies. Given the vast nature of the topic and the abundance of research that has emerged in the field of ASD over the last several years,⁴ providing an exhaustive review of each of the aspects discussed here is not within the scope of this article.

A comprehensive approach is essential

Multiple treatment modalities have been recommended for ASD.⁵ It is essential to address all aspects of ASD through cognitive, developmental, social-communication, sensory-motor, and behavioral interventions. Nonpharmacologic interventions are crucial in improving long-term outcomes of children with ASD.⁶

Nonpharmacologic treatments

Nonpharmacologic interventions commonly utilized for children with ASD include behavioral therapies, other psychological therapies, speech-language therapy, occupational therapy, educational interventions, parent coaching/training, developmental social interventions, and other modalities of therapy that are delivered in school, home, and clinic settings.^5,7

A recent study examining ASD treatment trends via caregivers’ reports (N = 5,122) from the SPARK (Simons Foundation Powering Autism Research for Knowledge) cohort in the United States reported that 80% of children received speech-language therapy or occupational therapy; 52% got both.⁵ The study revealed that approximately one-quarter utilized 3 therapies simultaneously; two-thirds had utilized 3 or more therapies in the previous year.⁵

Interventions for children with ASD need to be individualized.^1,8 Evidence-based behavioral interventions for ASD fall into 2 broad categories: Applied Behavior Analysis (ABA), and Naturalistic Developmental Behavioral Interventions (NDBI). Traditionally, ABA has been a key model, guiding treatment for enhancing social-communicating skills and lowering maladaptive behaviors in ASD.⁹ ABA follows a structured and prescribed format,^10,11 and has been shown to be efficacious.^1,7 More recently, NDBI, in which interventions are “embedded” in the natural environment of the young child and more actively incorporate a developmental perspective, has been shown to be beneficial in improving and generalizing social-communication skills in young children with ASD.^7,11

Early Start Denver Model (ESDM) is an intensive, naturalistic behavioral intervention⁴ that has been shown to be efficacious for enhancing communication and adaptive behavior in children with ASD.^7,8,12 A multisite randomized controlled trial (RCT) by Rogers et al¹² that examined the efficacy of ESDM in 118 children (age 14 to 24 months) with ASD found the treatment was beneficial and superior compared with a “community intervention” group, in regards to language ability measured in time by group analyses.The ESDM intervention in this study involved weekly parent coaching for 3 months, along with 24 months of 15 hours/week of one-on-one treatment provided by therapy professionals.¹²

Reciprocal imitation training (RIT) is another naturalistic intervention that has shown benefit in training children with ASD in imitation skills during play.¹³ Studies have found that both RIT and ESDM can be parent-implemented, after parents receive training.^13,14

Parent-mediated, parent-implemented interventions may have a role in improving outcomes in childhood ASD,^7,15 particularly “better generalization and maintenance of skills than therapist-implemented intervention” for lowering challenging behaviors and enhancing verbal and nonverbal communication.¹⁶

Various social skills interventions have also been found effective for children with ASD.¹ Such interventions are often provided in the school setting.⁷ Coordination with the child’s school to discuss and advocating for adequate and suitable interventions, educational services, and placement is an essential aspect of ASD treatment.⁷

Two other school-based, comprehensive treatment model interventions—Learning Experiences and Alternative Programs for Preschoolers and their Parents (LEAP), and TEACCH—have some evidence of leading to improvement in children with ASD.^7,17

Some studies have found that music therapy may have high efficacy for children with ASD, even with smaller length and intensity of treatment, particularly in improving social interaction, engagement with parents, joint attention, and communication.^3,18 Further research is needed to conclusively establish the efficacy of music therapy for ASD in children and adolescents.

A few studies have assessed the long-term outcomes of interventions for ASD; however, more research is needed.¹⁹ Pickles et al¹⁹ conducted a follow-up to determine the long-term effects of the Preschool Autism Communication Trial (PACT), an RCT of parent-mediated social communication therapy for children age 2 to 4 with ASD. The children’s average age at follow-up was 10 years. The authors found a significant long-term decrease in ASD symptoms and enhancement of social communication with parents (N = 152).¹⁹

Technology-based interventions, including games and robotics, have been investigated in recent years, for treatment of children with ASD (eg, for improving social skills).²⁰

Research suggests that the intensity (number of hours) and duration of nonpharmacologic treatments for ASD is critical to improving outcomes (Box^{1,3,5,7,10,16}).

Box

Continue to: Pharmacotherapy...

Pharmacotherapy

Medications cannot resolve core features of ASD.²¹ However, certain medications may help address associated comorbidities, such as attention-deficit/hyperactivity disorder (ADHD), depression, or others, when these conditions have not responded to nonpharmacologic interventions.^7,22 Common symptoms that are often treated with pharmacotherapy include aggression, irritability, hyperactivity, attentional difficulties, tics, self-injurious behavior, obsessive-compulsive symptoms, and mood dysregulation/lability.²³ Generally speaking, medications might be considered if symptoms are severe and markedly impair functioning. For mild to moderate conditions, psychotherapy and other nonpharmacologic interventions are generally considered first-line. Since none of the medications described below are specific to ASD and psychiatrists generally receive training in prescribing them for other indications, a comprehensive review of their risks and benefits is beyond the scope of this article. No psychotropic medications are known to have robust evidence for safety in preschool children with ASD, and thus are best avoided.

Antipsychotics. Risperidone (for age 5 and older) and aripiprazole (age 6 to 17) are the only medications FDA-approved for use in children and adolescents with ASD, specifically for irritability associated with ASD.^21,24 These 2 second-generation antipsychotics may also assist in lowering aggression in patients with ASD.²⁴ First-generation antipsychotics such as haloperidol have been shown to be effective for irritability and aggression in ASD, but the risk of significant adverse effects such as dyskinesias and extrapyramidal symptoms limit their use.²⁴ Two studies (a double-blind study and an open-label extension of that study) in children and adolescents with ASD found that risperidone was more effective and better tolerated than haloperidol in behavioral measures, impulsivity, and even in the social domain.^25,26 In addition to other adverse effects and risks, increased prolactin secondary to risperidone use requires close monitoring and caution.^24-26 As is the case with the use of other psychotropic medications in children and adolescents, those with ASD who receive antipsychotics should also be periodically reassessed to determine the need for continued use of these medications.²⁷ A multicenter relapse prevention RCT found no statistically significant difference in the time to relapse between aripiprazole and placebo.²⁷ Metabolic syndrome, cardiac risks, and other risks need to be considered before prescribing an antipsychotic.²⁸ Given their serious adverse effects profile, use should be considered only when there is severe impairment or risk of injury, after carefully weighing risks/benefits.

Medications for attentional difficulties. A multisite, randomized, placebo-controlled trial evaluating the use of extended-release guanfacine in children with ASD (N = 62) found the rate of positive response on the Clinical Global Impressions–Improvement scale was 50% for guanfacine vs 9.4% for placebo.²⁹ Clinicians need to monitor for adverse effects of guanfacine, such as fatigue, drowsiness, lightheadedness, lowering of blood pressure and heart rate, and other effects.²⁹ A randomized, double-blind trial of 97 children and adolescents with ASD and ADHD found that atomoxetine had moderate benefit for ADHD symptoms.³⁰ The study reported no serious adverse effects.³⁰ However, it is especially important to monitor for hepatic and cardiac adverse effects (in addition to monitoring for risk of increase in suicidal thoughts/behavior, as in the case of antidepressants) when using atomoxetine, in addition to other side effects and risks. Some evidence suggests that methylphenidate may be effective for attentional difficulties in children and adolescents with ASD²¹ but may pose a higher risk of adverse effects in this population compared with neurotypical patients.³¹

Antidepressants. Selective serotonin reuptake inhibitors (SSRIs) are sometimes used to reduce obsessive-compulsive symptoms, repetitive behavior, or depressive symptoms in children with ASD, but are not FDA-approved for children or adolescents with ASD. In general, there is inadequate evidence to support the use of SSRIs for ASD in children.^31-34 In addition, children with ASD may be at a greater risk of adverse effects from SSRIs.^32,34 Despite this, SSRIs are the most commonly prescribed psychotropic medications in children with ASD.³²

An RCT examining the efficacy of fluoxetine in 158 children and adolescents with ASD found no significant difference in Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) score after 14 weeks of treatment; activation was a common adverse effect.³⁵ A 2005 randomized, double-blind, placebo-controlled trial of 45 children/adolescents with ASD found that low-dose liquid fluoxetine was more effective than placebo for reducing repetitive behaviors in this population.³⁶ Larger studies are warranted to further evaluate the efficacy and safety of fluoxetine (and of SSRIs in general, particularly in the long term) for children and adolescents with ASD.³⁶ A 2009 randomized, placebo-controlled trial of 149 children with ASD revealed no significant difference between citalopram and placebo as measured by Clinical Global Impressions scale or CY-BOCS scores, and noted a significantly elevated likelihood of adverse effects.³⁷

Other antidepressants. There is insufficient evidence to support the use of any other antidepressants in children and adolescents with ASD. A few studies^38,39 have examined the use of venlafaxine in children with ASD; however, further research and controlled studies with large sample sizes are required to conclusively establish its benefits. There is a dearth of evidence examining the use of the tetracyclic antidepressant mirtazapine, or other classes of medications such as tricyclic antidepressants or mood stabilizers, in children with ASD; only a few small studies have assessed the efficacy and adverse effects of these medications for such patients.³¹

Polypharmacy. Although there is no evidence to support polypharmacy in children and adolescents with ASD, the practice appears to be rampant in these patients.^28,40 A 2013 retrospective, observational study of psychotropic medication use in children with ASD (N = 33,565) found that 64% were prescribed psychotropic medications, and 35% exhibited evidence of polypharmacy.⁴⁰ In this study, the total duration of polypharmacy averaged 525 days.⁴⁰ When addressing polypharmacy, systematic deprescribing or simplification of the psychotropic medication regimen may be needed,²⁸ while taking into account the patient’s complete clinical situation, including (but not limited to) tolerability of the medication regimen, presence or absence of current stressors, presence or absence of adequate supports, use of nonpharmacologic treatments where appropriate, and other factors.

More studies assessing the efficacy and safety of psychotropic medications for children and adolescents with ASD are needed,³² especially studies that evaluate the effects of long-term use, because evidence for pharmacologic treatments for children with ASD is mixed and insufficient.³³ There is also a need for evidence-based standards for prescribing psychotropic medications in children and adolescents with ASD.

Psychotropic medications, if used in ASD, should be used only in conjunction with other evidence-based treatment modalities, and not as monotherapy.²¹ Children and adolescents with ASD may be particularly susceptible to side effects or adverse effects of certain psychotropic medications.³¹ When considering medications, carefully weigh the risks and benefits.^7,21,24,28 Starting low and going slow is generally the preferred strategy.^31,32 As always, when recommending medications, discuss in detail with parents the potential side effects, benefits, risks, interactions, and alternatives.

Other agents. Several double-blind, placebo-controlled trials have evaluated using melatonin for sleep difficulties in children and adolescents with ASD.⁴¹ A randomized, placebo-controlled, 12-week trial that assessed 160 children with ASD and insomnia found that melatonin plus cognitive-behavioral therapy (CBT) was superior in efficacy to melatonin alone, CBT alone, or placebo.⁴¹

The evidence regarding oxytocin use for children with ASD is mixed.³¹ Some small studies have associated improvement in the social domain with its use. Guastella et al⁴² conducted a randomized, double-blind, placebo-controlled trial of oxytocin nasal spray for 16 participants (age 12 to 19) with ASD, and found oxytocin enhanced emotional identification. Gordon et al⁴³ conducted a functional MRI study of brain activity with oxytocin use in children with high-functioning ASD (N = 17). They found that oxytocin may augment “salience and hedonic evaluations of socially meaningful stimuli in children with ASD” and thus help social attunement. Further research is needed to evaluate the impact of oxytocin on social behavior.

Complementary and alternative medicine. Although there is limited and inconclusive evidence about the use of complementary and alternative medicine in children and adolescents with ASD, these therapies continue to be commonly used.^44-46 A recent survey of parents (N = 211) of children with ASD from academic ASD outpatient clinics in Germany found that 46% reported their child was using or had used some type of complementary and alternative medicine.⁴⁴ There is inadequate evidence to support the use of a gluten-free, casein-free diet for children/adolescents with ASD.⁴⁶ A recent cross-sectional study assessing supplement use in 210 children with ASD in Canada found that 75% used supplements, such as multivitamins (77.8%), vitamin D (44.9%), omega 3 (42.5%), probiotics (36.5%), and magnesium (28.1%), despite insufficient evidence to support their safety or efficacy for children with ASD.⁴⁷ Importantly, 33.5% of parents in this study reported that they did not inform the physician about all their child’s supplements.⁴⁷ Some of the reasons the parents in this study provided for not disclosing information about supplements to their physicians were “physician lack of knowledge,” “no benefit,” “too time-consuming,” and “scared of judgment.”⁴⁷ Semi-structured interviews of parents of 21 children with ASD in Australia revealed that parents found information on complementary and alternative medicine and therapies complex and often conflicting.⁴⁵ In addition to recommendations from health care professionals, evidence suggests that parents often consider the opinions of media, friends, and family when making a decision on using complementary and alternative medicine modalities for children/adolescents with ASD.⁴⁶ Such findings can inform physician practices regarding supplement use, and highlight the need to educate parents about the evidence regarding these therapies and potential adverse effects and interactions of such therapies,⁴⁶ along with the need to develop a centralized, evidence-based resource for parents regarding their use.⁴⁵

Omega 3 supplementation has in general shown few adverse effects⁴⁷; still, risks/benefits need to be weighed before use. Some evidence suggests that it may decrease hyperactivity in children with ASD.^31,48 However, further research, particularly controlled trials with large sample sizes, are needed for a definitive determination of efficacy.^31,48 A meta-analysis that included 27 RCTs assessing the efficacy of dietary interventions for various ASD symptoms found that omega 3 supplementation was more effective than placebo, but compared with placebo, the effect size was small.⁴⁹ A RCT of 73 children with ASD in New Zealand found that omega 3 long chain polyunsaturated fatty acids may benefit some core symptoms of ASD; the authors suggested that further research is needed to conclusively establish efficacy.⁵⁰

Continue to: A need for advocacy and research..

Physicians who treat children with ASD can not only make appropriate referrals and educate parents, but also educate their patients’ schools and advocate for their patients to get the level of services they need.^23,28

A recent study in the United States found that behavior therapy and speech-language therapy were used less often in the treatment of children with ASD in rural areas compared with those in metro areas.⁵ This suggests that in addition to increasing parents’ awareness and use of ASD services and providing referrals where appropriate, physicians are in a unique position to advocate for public health policies to improve access, coverage, and training for the provision of such services in rural areas.

There is need for ongoing research to further examine the efficacy and nuances of effects of various treatment interventions for ASD, especially long-term studies with larger sample sizes.^11,51 Additionally, research is warranted to better understand the underlying genetic and neurobiological mechanisms of ASD, which would help guide the development of biomarkers,⁵² innovative treatments, and disease-modifying agents for ASD.^7,22 Exploring the effects of potential alliances or joint action between biological and psychosocial interventions for ASD is also an area that needs further research.⁵¹

Bottom Line

A combination of treatment modalities (such as speech-language therapy, social skills training, behavior therapy/other psychotherapy, and occupational therapy for sensory sensitivities) is generally needed to improve the long-term outcomes of children and adolescents with autism spectrum disorder (ASD). In addition to the importance of early intervention, the intensity and duration of nonpharmacologic treatments are vital to improving outcomes in ASD.

SECOND OF 2 PARTS

Evidence supports the crucial role of early intervention and nonpharmacologic approaches

A large percentage of individuals with autism spectrum disorder (ASD) experience persisting significant social deficits in adulthood,¹ which often leads to isolation, depressive symptoms, and poor occupational and relationship functioning.^2,3 Childhood is a vital time for making the most significant and lasting changes that can improve functioning of individuals with ASD. Psychiatrists and other physicians who treat children are in a key role to influence outcomes of children at risk for or diagnosed with ASD.

This article provides updates on various aspects of ASD diagnosis and treatment (based on available evidence up to March 2020). Part 1 (Current Psychiatry, March 2022) focused on early detection and diagnosis. Here in Part 2, I describe an overview of treatment strategies. Given the vast nature of the topic and the abundance of research that has emerged in the field of ASD over the last several years,⁴ providing an exhaustive review of each of the aspects discussed here is not within the scope of this article.

A comprehensive approach is essential

Multiple treatment modalities have been recommended for ASD.⁵ It is essential to address all aspects of ASD through cognitive, developmental, social-communication, sensory-motor, and behavioral interventions. Nonpharmacologic interventions are crucial in improving long-term outcomes of children with ASD.⁶

Nonpharmacologic treatments

Nonpharmacologic interventions commonly utilized for children with ASD include behavioral therapies, other psychological therapies, speech-language therapy, occupational therapy, educational interventions, parent coaching/training, developmental social interventions, and other modalities of therapy that are delivered in school, home, and clinic settings.^5,7

A recent study examining ASD treatment trends via caregivers’ reports (N = 5,122) from the SPARK (Simons Foundation Powering Autism Research for Knowledge) cohort in the United States reported that 80% of children received speech-language therapy or occupational therapy; 52% got both.⁵ The study revealed that approximately one-quarter utilized 3 therapies simultaneously; two-thirds had utilized 3 or more therapies in the previous year.⁵

Interventions for children with ASD need to be individualized.^1,8 Evidence-based behavioral interventions for ASD fall into 2 broad categories: Applied Behavior Analysis (ABA), and Naturalistic Developmental Behavioral Interventions (NDBI). Traditionally, ABA has been a key model, guiding treatment for enhancing social-communicating skills and lowering maladaptive behaviors in ASD.⁹ ABA follows a structured and prescribed format,^10,11 and has been shown to be efficacious.^1,7 More recently, NDBI, in which interventions are “embedded” in the natural environment of the young child and more actively incorporate a developmental perspective, has been shown to be beneficial in improving and generalizing social-communication skills in young children with ASD.^7,11

Early Start Denver Model (ESDM) is an intensive, naturalistic behavioral intervention⁴ that has been shown to be efficacious for enhancing communication and adaptive behavior in children with ASD.^7,8,12 A multisite randomized controlled trial (RCT) by Rogers et al¹² that examined the efficacy of ESDM in 118 children (age 14 to 24 months) with ASD found the treatment was beneficial and superior compared with a “community intervention” group, in regards to language ability measured in time by group analyses.The ESDM intervention in this study involved weekly parent coaching for 3 months, along with 24 months of 15 hours/week of one-on-one treatment provided by therapy professionals.¹²

Reciprocal imitation training (RIT) is another naturalistic intervention that has shown benefit in training children with ASD in imitation skills during play.¹³ Studies have found that both RIT and ESDM can be parent-implemented, after parents receive training.^13,14

Parent-mediated, parent-implemented interventions may have a role in improving outcomes in childhood ASD,^7,15 particularly “better generalization and maintenance of skills than therapist-implemented intervention” for lowering challenging behaviors and enhancing verbal and nonverbal communication.¹⁶

Various social skills interventions have also been found effective for children with ASD.¹ Such interventions are often provided in the school setting.⁷ Coordination with the child’s school to discuss and advocating for adequate and suitable interventions, educational services, and placement is an essential aspect of ASD treatment.⁷

Two other school-based, comprehensive treatment model interventions—Learning Experiences and Alternative Programs for Preschoolers and their Parents (LEAP), and TEACCH—have some evidence of leading to improvement in children with ASD.^7,17

Some studies have found that music therapy may have high efficacy for children with ASD, even with smaller length and intensity of treatment, particularly in improving social interaction, engagement with parents, joint attention, and communication.^3,18 Further research is needed to conclusively establish the efficacy of music therapy for ASD in children and adolescents.

A few studies have assessed the long-term outcomes of interventions for ASD; however, more research is needed.¹⁹ Pickles et al¹⁹ conducted a follow-up to determine the long-term effects of the Preschool Autism Communication Trial (PACT), an RCT of parent-mediated social communication therapy for children age 2 to 4 with ASD. The children’s average age at follow-up was 10 years. The authors found a significant long-term decrease in ASD symptoms and enhancement of social communication with parents (N = 152).¹⁹

Technology-based interventions, including games and robotics, have been investigated in recent years, for treatment of children with ASD (eg, for improving social skills).²⁰

Research suggests that the intensity (number of hours) and duration of nonpharmacologic treatments for ASD is critical to improving outcomes (Box^{1,3,5,7,10,16}).

Box

Continue to: Pharmacotherapy...

Pharmacotherapy

Medications cannot resolve core features of ASD.²¹ However, certain medications may help address associated comorbidities, such as attention-deficit/hyperactivity disorder (ADHD), depression, or others, when these conditions have not responded to nonpharmacologic interventions.^7,22 Common symptoms that are often treated with pharmacotherapy include aggression, irritability, hyperactivity, attentional difficulties, tics, self-injurious behavior, obsessive-compulsive symptoms, and mood dysregulation/lability.²³ Generally speaking, medications might be considered if symptoms are severe and markedly impair functioning. For mild to moderate conditions, psychotherapy and other nonpharmacologic interventions are generally considered first-line. Since none of the medications described below are specific to ASD and psychiatrists generally receive training in prescribing them for other indications, a comprehensive review of their risks and benefits is beyond the scope of this article. No psychotropic medications are known to have robust evidence for safety in preschool children with ASD, and thus are best avoided.

Antipsychotics. Risperidone (for age 5 and older) and aripiprazole (age 6 to 17) are the only medications FDA-approved for use in children and adolescents with ASD, specifically for irritability associated with ASD.^21,24 These 2 second-generation antipsychotics may also assist in lowering aggression in patients with ASD.²⁴ First-generation antipsychotics such as haloperidol have been shown to be effective for irritability and aggression in ASD, but the risk of significant adverse effects such as dyskinesias and extrapyramidal symptoms limit their use.²⁴ Two studies (a double-blind study and an open-label extension of that study) in children and adolescents with ASD found that risperidone was more effective and better tolerated than haloperidol in behavioral measures, impulsivity, and even in the social domain.^25,26 In addition to other adverse effects and risks, increased prolactin secondary to risperidone use requires close monitoring and caution.^24-26 As is the case with the use of other psychotropic medications in children and adolescents, those with ASD who receive antipsychotics should also be periodically reassessed to determine the need for continued use of these medications.²⁷ A multicenter relapse prevention RCT found no statistically significant difference in the time to relapse between aripiprazole and placebo.²⁷ Metabolic syndrome, cardiac risks, and other risks need to be considered before prescribing an antipsychotic.²⁸ Given their serious adverse effects profile, use should be considered only when there is severe impairment or risk of injury, after carefully weighing risks/benefits.

Medications for attentional difficulties. A multisite, randomized, placebo-controlled trial evaluating the use of extended-release guanfacine in children with ASD (N = 62) found the rate of positive response on the Clinical Global Impressions–Improvement scale was 50% for guanfacine vs 9.4% for placebo.²⁹ Clinicians need to monitor for adverse effects of guanfacine, such as fatigue, drowsiness, lightheadedness, lowering of blood pressure and heart rate, and other effects.²⁹ A randomized, double-blind trial of 97 children and adolescents with ASD and ADHD found that atomoxetine had moderate benefit for ADHD symptoms.³⁰ The study reported no serious adverse effects.³⁰ However, it is especially important to monitor for hepatic and cardiac adverse effects (in addition to monitoring for risk of increase in suicidal thoughts/behavior, as in the case of antidepressants) when using atomoxetine, in addition to other side effects and risks. Some evidence suggests that methylphenidate may be effective for attentional difficulties in children and adolescents with ASD²¹ but may pose a higher risk of adverse effects in this population compared with neurotypical patients.³¹

Antidepressants. Selective serotonin reuptake inhibitors (SSRIs) are sometimes used to reduce obsessive-compulsive symptoms, repetitive behavior, or depressive symptoms in children with ASD, but are not FDA-approved for children or adolescents with ASD. In general, there is inadequate evidence to support the use of SSRIs for ASD in children.^31-34 In addition, children with ASD may be at a greater risk of adverse effects from SSRIs.^32,34 Despite this, SSRIs are the most commonly prescribed psychotropic medications in children with ASD.³²

An RCT examining the efficacy of fluoxetine in 158 children and adolescents with ASD found no significant difference in Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) score after 14 weeks of treatment; activation was a common adverse effect.³⁵ A 2005 randomized, double-blind, placebo-controlled trial of 45 children/adolescents with ASD found that low-dose liquid fluoxetine was more effective than placebo for reducing repetitive behaviors in this population.³⁶ Larger studies are warranted to further evaluate the efficacy and safety of fluoxetine (and of SSRIs in general, particularly in the long term) for children and adolescents with ASD.³⁶ A 2009 randomized, placebo-controlled trial of 149 children with ASD revealed no significant difference between citalopram and placebo as measured by Clinical Global Impressions scale or CY-BOCS scores, and noted a significantly elevated likelihood of adverse effects.³⁷

Other antidepressants. There is insufficient evidence to support the use of any other antidepressants in children and adolescents with ASD. A few studies^38,39 have examined the use of venlafaxine in children with ASD; however, further research and controlled studies with large sample sizes are required to conclusively establish its benefits. There is a dearth of evidence examining the use of the tetracyclic antidepressant mirtazapine, or other classes of medications such as tricyclic antidepressants or mood stabilizers, in children with ASD; only a few small studies have assessed the efficacy and adverse effects of these medications for such patients.³¹

Polypharmacy. Although there is no evidence to support polypharmacy in children and adolescents with ASD, the practice appears to be rampant in these patients.^28,40 A 2013 retrospective, observational study of psychotropic medication use in children with ASD (N = 33,565) found that 64% were prescribed psychotropic medications, and 35% exhibited evidence of polypharmacy.⁴⁰ In this study, the total duration of polypharmacy averaged 525 days.⁴⁰ When addressing polypharmacy, systematic deprescribing or simplification of the psychotropic medication regimen may be needed,²⁸ while taking into account the patient’s complete clinical situation, including (but not limited to) tolerability of the medication regimen, presence or absence of current stressors, presence or absence of adequate supports, use of nonpharmacologic treatments where appropriate, and other factors.

More studies assessing the efficacy and safety of psychotropic medications for children and adolescents with ASD are needed,³² especially studies that evaluate the effects of long-term use, because evidence for pharmacologic treatments for children with ASD is mixed and insufficient.³³ There is also a need for evidence-based standards for prescribing psychotropic medications in children and adolescents with ASD.

Psychotropic medications, if used in ASD, should be used only in conjunction with other evidence-based treatment modalities, and not as monotherapy.²¹ Children and adolescents with ASD may be particularly susceptible to side effects or adverse effects of certain psychotropic medications.³¹ When considering medications, carefully weigh the risks and benefits.^7,21,24,28 Starting low and going slow is generally the preferred strategy.^31,32 As always, when recommending medications, discuss in detail with parents the potential side effects, benefits, risks, interactions, and alternatives.

Other agents. Several double-blind, placebo-controlled trials have evaluated using melatonin for sleep difficulties in children and adolescents with ASD.⁴¹ A randomized, placebo-controlled, 12-week trial that assessed 160 children with ASD and insomnia found that melatonin plus cognitive-behavioral therapy (CBT) was superior in efficacy to melatonin alone, CBT alone, or placebo.⁴¹

The evidence regarding oxytocin use for children with ASD is mixed.³¹ Some small studies have associated improvement in the social domain with its use. Guastella et al⁴² conducted a randomized, double-blind, placebo-controlled trial of oxytocin nasal spray for 16 participants (age 12 to 19) with ASD, and found oxytocin enhanced emotional identification. Gordon et al⁴³ conducted a functional MRI study of brain activity with oxytocin use in children with high-functioning ASD (N = 17). They found that oxytocin may augment “salience and hedonic evaluations of socially meaningful stimuli in children with ASD” and thus help social attunement. Further research is needed to evaluate the impact of oxytocin on social behavior.

Complementary and alternative medicine. Although there is limited and inconclusive evidence about the use of complementary and alternative medicine in children and adolescents with ASD, these therapies continue to be commonly used.^44-46 A recent survey of parents (N = 211) of children with ASD from academic ASD outpatient clinics in Germany found that 46% reported their child was using or had used some type of complementary and alternative medicine.⁴⁴ There is inadequate evidence to support the use of a gluten-free, casein-free diet for children/adolescents with ASD.⁴⁶ A recent cross-sectional study assessing supplement use in 210 children with ASD in Canada found that 75% used supplements, such as multivitamins (77.8%), vitamin D (44.9%), omega 3 (42.5%), probiotics (36.5%), and magnesium (28.1%), despite insufficient evidence to support their safety or efficacy for children with ASD.⁴⁷ Importantly, 33.5% of parents in this study reported that they did not inform the physician about all their child’s supplements.⁴⁷ Some of the reasons the parents in this study provided for not disclosing information about supplements to their physicians were “physician lack of knowledge,” “no benefit,” “too time-consuming,” and “scared of judgment.”⁴⁷ Semi-structured interviews of parents of 21 children with ASD in Australia revealed that parents found information on complementary and alternative medicine and therapies complex and often conflicting.⁴⁵ In addition to recommendations from health care professionals, evidence suggests that parents often consider the opinions of media, friends, and family when making a decision on using complementary and alternative medicine modalities for children/adolescents with ASD.⁴⁶ Such findings can inform physician practices regarding supplement use, and highlight the need to educate parents about the evidence regarding these therapies and potential adverse effects and interactions of such therapies,⁴⁶ along with the need to develop a centralized, evidence-based resource for parents regarding their use.⁴⁵

Omega 3 supplementation has in general shown few adverse effects⁴⁷; still, risks/benefits need to be weighed before use. Some evidence suggests that it may decrease hyperactivity in children with ASD.^31,48 However, further research, particularly controlled trials with large sample sizes, are needed for a definitive determination of efficacy.^31,48 A meta-analysis that included 27 RCTs assessing the efficacy of dietary interventions for various ASD symptoms found that omega 3 supplementation was more effective than placebo, but compared with placebo, the effect size was small.⁴⁹ A RCT of 73 children with ASD in New Zealand found that omega 3 long chain polyunsaturated fatty acids may benefit some core symptoms of ASD; the authors suggested that further research is needed to conclusively establish efficacy.⁵⁰

Continue to: A need for advocacy and research..

Physicians who treat children with ASD can not only make appropriate referrals and educate parents, but also educate their patients’ schools and advocate for their patients to get the level of services they need.^23,28

A recent study in the United States found that behavior therapy and speech-language therapy were used less often in the treatment of children with ASD in rural areas compared with those in metro areas.⁵ This suggests that in addition to increasing parents’ awareness and use of ASD services and providing referrals where appropriate, physicians are in a unique position to advocate for public health policies to improve access, coverage, and training for the provision of such services in rural areas.

There is need for ongoing research to further examine the efficacy and nuances of effects of various treatment interventions for ASD, especially long-term studies with larger sample sizes.^11,51 Additionally, research is warranted to better understand the underlying genetic and neurobiological mechanisms of ASD, which would help guide the development of biomarkers,⁵² innovative treatments, and disease-modifying agents for ASD.^7,22 Exploring the effects of potential alliances or joint action between biological and psychosocial interventions for ASD is also an area that needs further research.⁵¹

Bottom Line

A combination of treatment modalities (such as speech-language therapy, social skills training, behavior therapy/other psychotherapy, and occupational therapy for sensory sensitivities) is generally needed to improve the long-term outcomes of children and adolescents with autism spectrum disorder (ASD). In addition to the importance of early intervention, the intensity and duration of nonpharmacologic treatments are vital to improving outcomes in ASD.

SECOND OF 2 PARTS

Evidence supports the crucial role of early intervention and nonpharmacologic approaches

A large percentage of individuals with autism spectrum disorder (ASD) experience persisting significant social deficits in adulthood,¹ which often leads to isolation, depressive symptoms, and poor occupational and relationship functioning.^2,3 Childhood is a vital time for making the most significant and lasting changes that can improve functioning of individuals with ASD. Psychiatrists and other physicians who treat children are in a key role to influence outcomes of children at risk for or diagnosed with ASD.

This article provides updates on various aspects of ASD diagnosis and treatment (based on available evidence up to March 2020). Part 1 (Current Psychiatry, March 2022) focused on early detection and diagnosis. Here in Part 2, I describe an overview of treatment strategies. Given the vast nature of the topic and the abundance of research that has emerged in the field of ASD over the last several years,⁴ providing an exhaustive review of each of the aspects discussed here is not within the scope of this article.

A comprehensive approach is essential

Multiple treatment modalities have been recommended for ASD.⁵ It is essential to address all aspects of ASD through cognitive, developmental, social-communication, sensory-motor, and behavioral interventions. Nonpharmacologic interventions are crucial in improving long-term outcomes of children with ASD.⁶

Nonpharmacologic treatments

Nonpharmacologic interventions commonly utilized for children with ASD include behavioral therapies, other psychological therapies, speech-language therapy, occupational therapy, educational interventions, parent coaching/training, developmental social interventions, and other modalities of therapy that are delivered in school, home, and clinic settings.^5,7

A recent study examining ASD treatment trends via caregivers’ reports (N = 5,122) from the SPARK (Simons Foundation Powering Autism Research for Knowledge) cohort in the United States reported that 80% of children received speech-language therapy or occupational therapy; 52% got both.⁵ The study revealed that approximately one-quarter utilized 3 therapies simultaneously; two-thirds had utilized 3 or more therapies in the previous year.⁵

Interventions for children with ASD need to be individualized.^1,8 Evidence-based behavioral interventions for ASD fall into 2 broad categories: Applied Behavior Analysis (ABA), and Naturalistic Developmental Behavioral Interventions (NDBI). Traditionally, ABA has been a key model, guiding treatment for enhancing social-communicating skills and lowering maladaptive behaviors in ASD.⁹ ABA follows a structured and prescribed format,^10,11 and has been shown to be efficacious.^1,7 More recently, NDBI, in which interventions are “embedded” in the natural environment of the young child and more actively incorporate a developmental perspective, has been shown to be beneficial in improving and generalizing social-communication skills in young children with ASD.^7,11

Early Start Denver Model (ESDM) is an intensive, naturalistic behavioral intervention⁴ that has been shown to be efficacious for enhancing communication and adaptive behavior in children with ASD.^7,8,12 A multisite randomized controlled trial (RCT) by Rogers et al¹² that examined the efficacy of ESDM in 118 children (age 14 to 24 months) with ASD found the treatment was beneficial and superior compared with a “community intervention” group, in regards to language ability measured in time by group analyses.The ESDM intervention in this study involved weekly parent coaching for 3 months, along with 24 months of 15 hours/week of one-on-one treatment provided by therapy professionals.¹²

Reciprocal imitation training (RIT) is another naturalistic intervention that has shown benefit in training children with ASD in imitation skills during play.¹³ Studies have found that both RIT and ESDM can be parent-implemented, after parents receive training.^13,14

Parent-mediated, parent-implemented interventions may have a role in improving outcomes in childhood ASD,^7,15 particularly “better generalization and maintenance of skills than therapist-implemented intervention” for lowering challenging behaviors and enhancing verbal and nonverbal communication.¹⁶

Various social skills interventions have also been found effective for children with ASD.¹ Such interventions are often provided in the school setting.⁷ Coordination with the child’s school to discuss and advocating for adequate and suitable interventions, educational services, and placement is an essential aspect of ASD treatment.⁷

Two other school-based, comprehensive treatment model interventions—Learning Experiences and Alternative Programs for Preschoolers and their Parents (LEAP), and TEACCH—have some evidence of leading to improvement in children with ASD.^7,17

Some studies have found that music therapy may have high efficacy for children with ASD, even with smaller length and intensity of treatment, particularly in improving social interaction, engagement with parents, joint attention, and communication.^3,18 Further research is needed to conclusively establish the efficacy of music therapy for ASD in children and adolescents.

A few studies have assessed the long-term outcomes of interventions for ASD; however, more research is needed.¹⁹ Pickles et al¹⁹ conducted a follow-up to determine the long-term effects of the Preschool Autism Communication Trial (PACT), an RCT of parent-mediated social communication therapy for children age 2 to 4 with ASD. The children’s average age at follow-up was 10 years. The authors found a significant long-term decrease in ASD symptoms and enhancement of social communication with parents (N = 152).¹⁹

Technology-based interventions, including games and robotics, have been investigated in recent years, for treatment of children with ASD (eg, for improving social skills).²⁰

Research suggests that the intensity (number of hours) and duration of nonpharmacologic treatments for ASD is critical to improving outcomes (Box^{1,3,5,7,10,16}).

Box

Continue to: Pharmacotherapy...

Pharmacotherapy

Medications cannot resolve core features of ASD.²¹ However, certain medications may help address associated comorbidities, such as attention-deficit/hyperactivity disorder (ADHD), depression, or others, when these conditions have not responded to nonpharmacologic interventions.^7,22 Common symptoms that are often treated with pharmacotherapy include aggression, irritability, hyperactivity, attentional difficulties, tics, self-injurious behavior, obsessive-compulsive symptoms, and mood dysregulation/lability.²³ Generally speaking, medications might be considered if symptoms are severe and markedly impair functioning. For mild to moderate conditions, psychotherapy and other nonpharmacologic interventions are generally considered first-line. Since none of the medications described below are specific to ASD and psychiatrists generally receive training in prescribing them for other indications, a comprehensive review of their risks and benefits is beyond the scope of this article. No psychotropic medications are known to have robust evidence for safety in preschool children with ASD, and thus are best avoided.

Antipsychotics. Risperidone (for age 5 and older) and aripiprazole (age 6 to 17) are the only medications FDA-approved for use in children and adolescents with ASD, specifically for irritability associated with ASD.^21,24 These 2 second-generation antipsychotics may also assist in lowering aggression in patients with ASD.²⁴ First-generation antipsychotics such as haloperidol have been shown to be effective for irritability and aggression in ASD, but the risk of significant adverse effects such as dyskinesias and extrapyramidal symptoms limit their use.²⁴ Two studies (a double-blind study and an open-label extension of that study) in children and adolescents with ASD found that risperidone was more effective and better tolerated than haloperidol in behavioral measures, impulsivity, and even in the social domain.^25,26 In addition to other adverse effects and risks, increased prolactin secondary to risperidone use requires close monitoring and caution.^24-26 As is the case with the use of other psychotropic medications in children and adolescents, those with ASD who receive antipsychotics should also be periodically reassessed to determine the need for continued use of these medications.²⁷ A multicenter relapse prevention RCT found no statistically significant difference in the time to relapse between aripiprazole and placebo.²⁷ Metabolic syndrome, cardiac risks, and other risks need to be considered before prescribing an antipsychotic.²⁸ Given their serious adverse effects profile, use should be considered only when there is severe impairment or risk of injury, after carefully weighing risks/benefits.

Medications for attentional difficulties. A multisite, randomized, placebo-controlled trial evaluating the use of extended-release guanfacine in children with ASD (N = 62) found the rate of positive response on the Clinical Global Impressions–Improvement scale was 50% for guanfacine vs 9.4% for placebo.²⁹ Clinicians need to monitor for adverse effects of guanfacine, such as fatigue, drowsiness, lightheadedness, lowering of blood pressure and heart rate, and other effects.²⁹ A randomized, double-blind trial of 97 children and adolescents with ASD and ADHD found that atomoxetine had moderate benefit for ADHD symptoms.³⁰ The study reported no serious adverse effects.³⁰ However, it is especially important to monitor for hepatic and cardiac adverse effects (in addition to monitoring for risk of increase in suicidal thoughts/behavior, as in the case of antidepressants) when using atomoxetine, in addition to other side effects and risks. Some evidence suggests that methylphenidate may be effective for attentional difficulties in children and adolescents with ASD²¹ but may pose a higher risk of adverse effects in this population compared with neurotypical patients.³¹

Antidepressants. Selective serotonin reuptake inhibitors (SSRIs) are sometimes used to reduce obsessive-compulsive symptoms, repetitive behavior, or depressive symptoms in children with ASD, but are not FDA-approved for children or adolescents with ASD. In general, there is inadequate evidence to support the use of SSRIs for ASD in children.^31-34 In addition, children with ASD may be at a greater risk of adverse effects from SSRIs.^32,34 Despite this, SSRIs are the most commonly prescribed psychotropic medications in children with ASD.³²

An RCT examining the efficacy of fluoxetine in 158 children and adolescents with ASD found no significant difference in Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) score after 14 weeks of treatment; activation was a common adverse effect.³⁵ A 2005 randomized, double-blind, placebo-controlled trial of 45 children/adolescents with ASD found that low-dose liquid fluoxetine was more effective than placebo for reducing repetitive behaviors in this population.³⁶ Larger studies are warranted to further evaluate the efficacy and safety of fluoxetine (and of SSRIs in general, particularly in the long term) for children and adolescents with ASD.³⁶ A 2009 randomized, placebo-controlled trial of 149 children with ASD revealed no significant difference between citalopram and placebo as measured by Clinical Global Impressions scale or CY-BOCS scores, and noted a significantly elevated likelihood of adverse effects.³⁷

Other antidepressants. There is insufficient evidence to support the use of any other antidepressants in children and adolescents with ASD. A few studies^38,39 have examined the use of venlafaxine in children with ASD; however, further research and controlled studies with large sample sizes are required to conclusively establish its benefits. There is a dearth of evidence examining the use of the tetracyclic antidepressant mirtazapine, or other classes of medications such as tricyclic antidepressants or mood stabilizers, in children with ASD; only a few small studies have assessed the efficacy and adverse effects of these medications for such patients.³¹

Polypharmacy. Although there is no evidence to support polypharmacy in children and adolescents with ASD, the practice appears to be rampant in these patients.^28,40 A 2013 retrospective, observational study of psychotropic medication use in children with ASD (N = 33,565) found that 64% were prescribed psychotropic medications, and 35% exhibited evidence of polypharmacy.⁴⁰ In this study, the total duration of polypharmacy averaged 525 days.⁴⁰ When addressing polypharmacy, systematic deprescribing or simplification of the psychotropic medication regimen may be needed,²⁸ while taking into account the patient’s complete clinical situation, including (but not limited to) tolerability of the medication regimen, presence or absence of current stressors, presence or absence of adequate supports, use of nonpharmacologic treatments where appropriate, and other factors.

More studies assessing the efficacy and safety of psychotropic medications for children and adolescents with ASD are needed,³² especially studies that evaluate the effects of long-term use, because evidence for pharmacologic treatments for children with ASD is mixed and insufficient.³³ There is also a need for evidence-based standards for prescribing psychotropic medications in children and adolescents with ASD.

Psychotropic medications, if used in ASD, should be used only in conjunction with other evidence-based treatment modalities, and not as monotherapy.²¹ Children and adolescents with ASD may be particularly susceptible to side effects or adverse effects of certain psychotropic medications.³¹ When considering medications, carefully weigh the risks and benefits.^7,21,24,28 Starting low and going slow is generally the preferred strategy.^31,32 As always, when recommending medications, discuss in detail with parents the potential side effects, benefits, risks, interactions, and alternatives.

Other agents. Several double-blind, placebo-controlled trials have evaluated using melatonin for sleep difficulties in children and adolescents with ASD.⁴¹ A randomized, placebo-controlled, 12-week trial that assessed 160 children with ASD and insomnia found that melatonin plus cognitive-behavioral therapy (CBT) was superior in efficacy to melatonin alone, CBT alone, or placebo.⁴¹

The evidence regarding oxytocin use for children with ASD is mixed.³¹ Some small studies have associated improvement in the social domain with its use. Guastella et al⁴² conducted a randomized, double-blind, placebo-controlled trial of oxytocin nasal spray for 16 participants (age 12 to 19) with ASD, and found oxytocin enhanced emotional identification. Gordon et al⁴³ conducted a functional MRI study of brain activity with oxytocin use in children with high-functioning ASD (N = 17). They found that oxytocin may augment “salience and hedonic evaluations of socially meaningful stimuli in children with ASD” and thus help social attunement. Further research is needed to evaluate the impact of oxytocin on social behavior.

Complementary and alternative medicine. Although there is limited and inconclusive evidence about the use of complementary and alternative medicine in children and adolescents with ASD, these therapies continue to be commonly used.^44-46 A recent survey of parents (N = 211) of children with ASD from academic ASD outpatient clinics in Germany found that 46% reported their child was using or had used some type of complementary and alternative medicine.⁴⁴ There is inadequate evidence to support the use of a gluten-free, casein-free diet for children/adolescents with ASD.⁴⁶ A recent cross-sectional study assessing supplement use in 210 children with ASD in Canada found that 75% used supplements, such as multivitamins (77.8%), vitamin D (44.9%), omega 3 (42.5%), probiotics (36.5%), and magnesium (28.1%), despite insufficient evidence to support their safety or efficacy for children with ASD.⁴⁷ Importantly, 33.5% of parents in this study reported that they did not inform the physician about all their child’s supplements.⁴⁷ Some of the reasons the parents in this study provided for not disclosing information about supplements to their physicians were “physician lack of knowledge,” “no benefit,” “too time-consuming,” and “scared of judgment.”⁴⁷ Semi-structured interviews of parents of 21 children with ASD in Australia revealed that parents found information on complementary and alternative medicine and therapies complex and often conflicting.⁴⁵ In addition to recommendations from health care professionals, evidence suggests that parents often consider the opinions of media, friends, and family when making a decision on using complementary and alternative medicine modalities for children/adolescents with ASD.⁴⁶ Such findings can inform physician practices regarding supplement use, and highlight the need to educate parents about the evidence regarding these therapies and potential adverse effects and interactions of such therapies,⁴⁶ along with the need to develop a centralized, evidence-based resource for parents regarding their use.⁴⁵

Omega 3 supplementation has in general shown few adverse effects⁴⁷; still, risks/benefits need to be weighed before use. Some evidence suggests that it may decrease hyperactivity in children with ASD.^31,48 However, further research, particularly controlled trials with large sample sizes, are needed for a definitive determination of efficacy.^31,48 A meta-analysis that included 27 RCTs assessing the efficacy of dietary interventions for various ASD symptoms found that omega 3 supplementation was more effective than placebo, but compared with placebo, the effect size was small.⁴⁹ A RCT of 73 children with ASD in New Zealand found that omega 3 long chain polyunsaturated fatty acids may benefit some core symptoms of ASD; the authors suggested that further research is needed to conclusively establish efficacy.⁵⁰

Continue to: A need for advocacy and research..

Physicians who treat children with ASD can not only make appropriate referrals and educate parents, but also educate their patients’ schools and advocate for their patients to get the level of services they need.^23,28

A recent study in the United States found that behavior therapy and speech-language therapy were used less often in the treatment of children with ASD in rural areas compared with those in metro areas.⁵ This suggests that in addition to increasing parents’ awareness and use of ASD services and providing referrals where appropriate, physicians are in a unique position to advocate for public health policies to improve access, coverage, and training for the provision of such services in rural areas.

There is need for ongoing research to further examine the efficacy and nuances of effects of various treatment interventions for ASD, especially long-term studies with larger sample sizes.^11,51 Additionally, research is warranted to better understand the underlying genetic and neurobiological mechanisms of ASD, which would help guide the development of biomarkers,⁵² innovative treatments, and disease-modifying agents for ASD.^7,22 Exploring the effects of potential alliances or joint action between biological and psychosocial interventions for ASD is also an area that needs further research.⁵¹

Bottom Line

A combination of treatment modalities (such as speech-language therapy, social skills training, behavior therapy/other psychotherapy, and occupational therapy for sensory sensitivities) is generally needed to improve the long-term outcomes of children and adolescents with autism spectrum disorder (ASD). In addition to the importance of early intervention, the intensity and duration of nonpharmacologic treatments are vital to improving outcomes in ASD.

COVID-19 affected all aspects of psychiatric care. As a psychiatrist who is also a psychoanalyst, I faced some unique challenges to caring for my patients during the pandemic. In this article, I describe how COVID-19 impacted my practice, and how I adjusted to ensure that my patients received the best possible care.

The loss of ‘normal’

Our recognition of the loss was not immediate since no one knew what to expect. From March 11, 2020 through the end of the warm weather, when we could be outdoors, personal life was still gratifying. There was even a new spirit of togetherness in my neighborhood, with people seamlessly cooperating by crossing the street to avoid getting too close to one another, practicing proper social distancing in the grocery line, and smiling at everyone.

November 2020 through Spring 2021 was an unprecedented period of no socialization and spending time exclusively with my husband. By the end, I was finally aware of the exhaustion I felt trying to work with patients via phone and video sessions. Beyond that, we were (and still are) conducting administrative meetings and national organization meetings by video.

Spring 2021 until the arrival of cold weather felt more relaxed, as socializing outside again became possible. But from Winter 2021 to now has been a weary repeat of isolation, and a realization that my work life might never go back to “normal.” I would have to make peace with various sorts of losses of gratification in my work.

Life before COVID-19

I am a psychiatrist and psychoanalyst in a group private practice near the University of Cincinnati Medical Center. As a former full-time faculty member there, I maintain some teaching and supervision of residents. I typically see patients from 8:30 AM until 6:30 PM, and for years have had an average of 5 patients in psychoanalysis on the couch for 3 to 4 sessions per week. I see some psychotherapy patients weekly or twice a week and have some hours for new diagnostic evaluations and medication management. In addition, as a faculty member of the Cincinnati Psychoanalytic Institute, I take part in several committees, teach in the psychotherapy program and psychoanalytic training program, and supervise students and candidates. Most weeks, I see between 35 and 40 patients, with 4 to 6 weeks of vacation time per year.

Major changes with the onset of the pandemic

Once the threat from COVID-19 became clear in March 2020, I thought through my options. My office comprises 5 professional offices, a waiting room, and an administrative area. Our administrative assistant and 1 or 2 practitioners were in the office with me most days. We maintained appropriate distance from each another and wore masks in common areas. The practice group was exemplary in immediately setting up safe practices. I learned a few colleagues were seeing patients outside using lawn chairs in the back of our lot where there was some privacy, but many stopped coming to the building altogether.

I felt real sadness having to tell patients I could no longer see them in my office. However, I was relieved to find how quickly many patients made an immediate transition to telephone or video sessions. Since I was alone in my office and not distracted by barking dogs, ringing doorbells, or loud lawnmowers, I continued to come to the office, and never switched to working from home.

Since I was not vis-à-vis with patients on the couch, those sessions shifted to the telephone. I offered psychotherapy patients the option of video sessions via the Health Insurance Portability and Accountability Act–compliant Doximity app (doxy.me) or telephone, and found that approximately 75% preferred video. When I used the telephone, I used a professional-grade headset, which made it less onerous than being tied to a receiver, and I occasionally used the speaker option. I also installed a desk platform that allows me to raise and lower my computer from sitting to standing height.

I worried a great deal about patients I felt would do poorly with video or telephone sessions: older adults who found comfort in human contact that was sometimes curative, less well-integrated individuals who needed real contact in order to feel there was a treatment process, those with serious mental illnesses who needed reassurance at their reality-testing, and new patients who I couldn’t fully assess without in-person meetings.

In the beginning of the pandemic, as we were still learning about the virus, nothing seemed safe. We were washing our hands constantly, afraid to touch doorknobs, mail, or groceries. Thankfully, we learned that COVID-19 transmission occurs primarily through inhalation of droplets and particles containing the virus.¹ Masks, good ventilation, and adequate distance from others considerably cut infection rates. By January 2021, the availability of a vaccine made an enormous difference in vulnerability to severe illness.

When I stopped seeing patients in my office, I set up the conference room that had doors on either end so I could sit on one end of a table and have the patient at the other end, keeping about 8 feet between us. I also kept a fan blowing air away from me and parallel to the patient. After each session, I opened both doors to allow for full ventilation of the room. This provided a solution for the patients I knew I needed to meet with in person.

The following case examples illustrate how I provided care during this time. To protect patient anonymity, these vignettes are composites.

Psychotherapy patients 

Established patients in psychotherapy have seemed to work well with video or telephone sessions. The video option added a new element I never appreciated: seeing patients in their homes or cars allowed me to gain a new set of impressions about them. The use of technology is clearly another element I would not have identified before. Less technically adept older patients are likely to join a video session with only the top of their head visible, or with insufficient lighting. In some cases, I coached patients to rearrange their computer so I could see their faces, but only if it seemed that doing so would not cause them greater distress.

Ms. A, age 74, is a widow who retired from a high-level professional position 5 years ago. She was brought to the hospital due to ongoing anxiety, especially about her health. Ms. A maintained a wide range of relationships with friends, colleagues she mentored, and neighbors who provided a satisfying social network, and she continued to contribute to her field via scholarly writing projects. Before the pandemic, she found occasional sessions helpful in putting her health fears into perspective. When the pandemic led her to isolate at home, Ms. A became anxious and depressed to an unprecedented extent. Video sessions were unsatisfying, and she was terrified of taking tranquilizers or other medications. Once COVID-19 vaccinations became available and both she and I received both doses, we switched to meeting in the conference room every 2 to 3 weeks, with considerably better results.

Mr. B, age 41, is a single male who I diagnosed with schizophrenia at age 19 when he developed paranoid delusions and auditory hallucinations. Mr. B was not interested in taking antipsychotic medications, and his situation did not improve even when he did try taking them. He volunteered at a local emergency department doing odd jobs—moving gurneys, cleaning rooms, hauling boxes of supplies—for many years, and had always been employed in jobs such as grocery stocking or janitorial work that did not involve extensive interactions with people. He repeatedly enrolled in programs that would provide a skill such as phlebotomy or medical billing, only to find that he was never hired for such work. We talked once a month for 30 minutes about his frustrations trying to find women to date and marry, and how he was repeatedly taken advantage of (one “date” from an escort service took him to an ATM and got him to withdraw most of the money in his account).

Coincident with COVID-19, Mr. B’s father died from widespread metastatic cancer. His father had been Mr. B’s guide, friend, payee for Social Security Disability Insurance funds, and source of advice. To provide humane and somewhat effective treatment, I saw Mr. B in the conference room. His capacity to express grief and distress at the loss of his father has been impressive, as has his initiative in finding a grief group to attend, which he has done consistently.

Several patients who had been seeing me for weekly psychotherapy chose not to continue, many without specifically informing me of their decision. I understood the situation was in flux, and it would not be clear to anyone what to expect for the future. To avoid pressuring anyone, I chose not to contact patients to inquire about their plans.

Ms. C, age 50, is a professional with 3 children whose marriage had been highly dissatisfying for years, and she was now ready to investigate it. She was very successful in her career, having taken on a leadership role in her firm and earning a high income, while her husband was erratic, unreliable, and self-absorbed. Though he was well-educated and competent in his field, he could not maintain employment in a corporate environment and worked as a consultant with relatively little success. Along with the hours she spent working, Ms. C took responsibility for the family finances, was the chief wage earner, managed the needs of their children, made sure meals were prepared, and took on many other responsibilities.

Continue to: Case examples: How it worked (cont.)...

We agreed to a weekly session that fit Ms. C’s schedule, and she seemed able to relax and talk about herself. I found Ms. C quite likeable and enjoyed meeting with her, though I worried about whether we would need a greater intensity to get at the reasons such a successful and intelligent woman would fear setting limits with her husband or even considering ending the relationship. The reasons were clear as we put together the story of her early life, but conviction only develops with full emotional awareness (transference provides this in psychoanalysis).

The pandemic started approximately 18 months into our work, and Ms. C disappeared. She called my administrative assistant to cancel further appointments but did not ask to speak with me directly. While I knew this might represent resistance, I also felt unwilling to pressure Ms. C if she chose not to continue. I remain hopeful that I will hear from her once again; if not, I will send a note by mail to say that I enjoyed working with her, am happy to see her again, and hope she found some benefit from our work.

Mr. D contacted me for psychotherapy following the death of his father, who I had seen as a patient many years earlier. I was aware of the likely impact of his father’s outsized personality and emotional dysregulation on Mr. D and agreed to meet with him. He had taken over the family business and had made it an even greater success, but had trouble feeling confident about setting limits with employees who he knew took advantage of his avoidance.

Mr. D and I met weekly for several months and then moved to every other week, a form of resistance I expected as we got closer to his feeling pain. At the same time, I recognize that many patients use this tactic to “dose” themselves with the intensity they can tolerate, and Mr. D was quite observant and able to pick up themes where we’d left off.

When the pandemic shut down office visits, Mr. D immediately agreed to video sessions, which he has continued at roughly the same frequency. While I miss sitting with him, we continue to make progress towards his goal of learning to see himself as able to compete with his father.

Psychoanalysis patients 

I found that patients in psychoanalysis had no trouble with the transition to telephone sessions, and the intensity of the work was not diluted. In some ways, audio-only communication is more intimate and might encourage patients to talk about topics they may not have otherwise brought up. I have not seen any evidence of less progress among these patients.

Dr. E, age 45, is a divorced physician who began psychoanalysis 3 times per week on the couch in 2018 for problems with frustration and confusion about his career, his identity as a father, and intense loneliness. He had worked up to 80 hours per week to earn as much money as he could, but also to avoid time at home with his then-wife and young children. The lack of time to recover led him to hate his work, left no time for social connections, and led to binges of heavy drinking. Our work had begun to allow him to develop a narrative about his early life that had never been considered, and to identify patterns of repetition of old defensive strategies that had never served him well.

At the onset of the pandemic, I told Dr. E that we would have to switch to telephone sessions, and he agreed immediately. In fact, he came to prefer telephone work since it spared him the 2 hours per day he had spent coming to my office. While I found it less satisfying than working in person, we have continued the same schedule and with the same intensity and trajectory established before the pandemic.

Continue to: Working with new patients...

Seeing new patients for diagnostic evaluation is always best done in person, because the information I gain from the patient’s appearance, clothing, demeanor, gait, postures, gesturing, and facial expressions (among other elements) gives me important impressions I miss with video or telephone. In many cases, patients gain a sense of who I am from sitting in my office, and using the conference room eliminates that benefit. I attempted to create a warm environment in the conference room by obtaining lamps that produce warmer indirect light and hanging artwork that reflects my tastes. There are clocks in places that allow me and my patient to keep track of time. In meeting new patients by video, I get some impressions about their surroundings that add to the information I get through our interview. I have done many diagnostic evaluations during the pandemic and gotten treatments (whether medication, psychotherapy, or both) underway without discernible problems in the outcomes. Patients who started with me in person have mostly wanted to continue with in-person meetings, but as many have told me, interspersed video sessions save them travel time.

What about vaccination?

Once COVID-19 vaccinations were widely available, I assumed patients would be as eager to get them as I had been. When I began asking patients about whether they had gotten their vaccines, I was surprised to hear that a few were not going to get vaccinated, clearly based on political views and misinformation about the danger of vaccines. (The topic of political beliefs and their impact on psychological treatment is beyond the scope of this commentary.) I tried to counter obvious misinformation, repeated my recommendation that the patient get vaccinated, and then turned to other topics. I later decided to tell all patients that vaccination was required to enter the office. Only 1 patient who had been coming to the office dropped out, and she eventually returned to meeting by video.

COVID-19’s toll on the therapist

While the first several months of the pandemic were so full of uncertainty about the future, once vaccinations were available, it seemed cause for hope of a return to normalcy. As time went on, however, it became clear that normal was still a long way off. With vaccine refusal and new variants upending my naïve view that we were near the end, I began to feel aware of the impact this had on me, and began to focus on self-care (Box). I had always seen myself as unusually lucky to have a full practice, a supportive partnership with my husband, grown children who didn’t need me to homeschool them, a strong social network of friends who could share the burden and cheer each other up at outdoor gatherings, and a wonderful group of siblings and in-laws (all in different cities) who stayed in touch via video calls and quarantined in advance of getting together in someone’s home.

Box

Staying busy and engaged with my practice, spouse, family, and friends kept sadness away most of the time. But I surprised myself a few months ago when I sat down to reflect and check in with myself. I felt enormous loss, resentment, and exhaustion at the privations of the pandemic: every trip to the grocery story felt dangerous. I hadn’t seen the inside of a concert hall, movie theater, restaurant, or museum in nearly 2 years. Travel for meetings and visits to family and friends and various adventures had been abruptly stopped. I lost both parents (not to COVID-19) during 2020; both were older adults living in senior communities that could not allow visitors. The usual grieving process would include attending services at my synagogue where I could say Kaddish for them, and video services were simply not tolerable.

Most of us have become experts at video meetings and likely have come to despise them. While our Institute has always held classes with some out-of-town students joining by video, with a very sophisticated system that provides excellent sound and visual fidelity, teaching entirely by video is another matter. I now teach students I have never met in person and might not recognize if I passed them in public. The art of creating discussion around a table is much more difficult on a computer screen. The first class I taught to residents during the pandemic was completely disorienting as I faced a wall of black screens with names and silence. Each student had turned off their camera and muted their microphone, so I was lecturing to a computer. That never happened again after I insisted on seeing everyone’s face and hearing their voices.

Thankfully, my usual experience of a long day seeing patients followed by chatting while cooking dinner with my husband and walking the dogs before settling down to read didn’t change. But the pleasure of sitting with patients was replaced by the daily grind of figuring out who will need a video link, who will be on the telephone, and who will come to the office, and it doesn’t feel the same. Again, in the big picture, I realize how fortunate I have been, but it’s been a big change in the world of the psychotherapist.

COVID-19 affected all aspects of psychiatric care. As a psychiatrist who is also a psychoanalyst, I faced some unique challenges to caring for my patients during the pandemic. In this article, I describe how COVID-19 impacted my practice, and how I adjusted to ensure that my patients received the best possible care.

The loss of ‘normal’

Our recognition of the loss was not immediate since no one knew what to expect. From March 11, 2020 through the end of the warm weather, when we could be outdoors, personal life was still gratifying. There was even a new spirit of togetherness in my neighborhood, with people seamlessly cooperating by crossing the street to avoid getting too close to one another, practicing proper social distancing in the grocery line, and smiling at everyone.

November 2020 through Spring 2021 was an unprecedented period of no socialization and spending time exclusively with my husband. By the end, I was finally aware of the exhaustion I felt trying to work with patients via phone and video sessions. Beyond that, we were (and still are) conducting administrative meetings and national organization meetings by video.

Spring 2021 until the arrival of cold weather felt more relaxed, as socializing outside again became possible. But from Winter 2021 to now has been a weary repeat of isolation, and a realization that my work life might never go back to “normal.” I would have to make peace with various sorts of losses of gratification in my work.

Life before COVID-19

I am a psychiatrist and psychoanalyst in a group private practice near the University of Cincinnati Medical Center. As a former full-time faculty member there, I maintain some teaching and supervision of residents. I typically see patients from 8:30 AM until 6:30 PM, and for years have had an average of 5 patients in psychoanalysis on the couch for 3 to 4 sessions per week. I see some psychotherapy patients weekly or twice a week and have some hours for new diagnostic evaluations and medication management. In addition, as a faculty member of the Cincinnati Psychoanalytic Institute, I take part in several committees, teach in the psychotherapy program and psychoanalytic training program, and supervise students and candidates. Most weeks, I see between 35 and 40 patients, with 4 to 6 weeks of vacation time per year.

Major changes with the onset of the pandemic

Once the threat from COVID-19 became clear in March 2020, I thought through my options. My office comprises 5 professional offices, a waiting room, and an administrative area. Our administrative assistant and 1 or 2 practitioners were in the office with me most days. We maintained appropriate distance from each another and wore masks in common areas. The practice group was exemplary in immediately setting up safe practices. I learned a few colleagues were seeing patients outside using lawn chairs in the back of our lot where there was some privacy, but many stopped coming to the building altogether.

I felt real sadness having to tell patients I could no longer see them in my office. However, I was relieved to find how quickly many patients made an immediate transition to telephone or video sessions. Since I was alone in my office and not distracted by barking dogs, ringing doorbells, or loud lawnmowers, I continued to come to the office, and never switched to working from home.

Since I was not vis-à-vis with patients on the couch, those sessions shifted to the telephone. I offered psychotherapy patients the option of video sessions via the Health Insurance Portability and Accountability Act–compliant Doximity app (doxy.me) or telephone, and found that approximately 75% preferred video. When I used the telephone, I used a professional-grade headset, which made it less onerous than being tied to a receiver, and I occasionally used the speaker option. I also installed a desk platform that allows me to raise and lower my computer from sitting to standing height.

I worried a great deal about patients I felt would do poorly with video or telephone sessions: older adults who found comfort in human contact that was sometimes curative, less well-integrated individuals who needed real contact in order to feel there was a treatment process, those with serious mental illnesses who needed reassurance at their reality-testing, and new patients who I couldn’t fully assess without in-person meetings.

In the beginning of the pandemic, as we were still learning about the virus, nothing seemed safe. We were washing our hands constantly, afraid to touch doorknobs, mail, or groceries. Thankfully, we learned that COVID-19 transmission occurs primarily through inhalation of droplets and particles containing the virus.¹ Masks, good ventilation, and adequate distance from others considerably cut infection rates. By January 2021, the availability of a vaccine made an enormous difference in vulnerability to severe illness.

When I stopped seeing patients in my office, I set up the conference room that had doors on either end so I could sit on one end of a table and have the patient at the other end, keeping about 8 feet between us. I also kept a fan blowing air away from me and parallel to the patient. After each session, I opened both doors to allow for full ventilation of the room. This provided a solution for the patients I knew I needed to meet with in person.

The following case examples illustrate how I provided care during this time. To protect patient anonymity, these vignettes are composites.

Psychotherapy patients 

Established patients in psychotherapy have seemed to work well with video or telephone sessions. The video option added a new element I never appreciated: seeing patients in their homes or cars allowed me to gain a new set of impressions about them. The use of technology is clearly another element I would not have identified before. Less technically adept older patients are likely to join a video session with only the top of their head visible, or with insufficient lighting. In some cases, I coached patients to rearrange their computer so I could see their faces, but only if it seemed that doing so would not cause them greater distress.

Ms. A, age 74, is a widow who retired from a high-level professional position 5 years ago. She was brought to the hospital due to ongoing anxiety, especially about her health. Ms. A maintained a wide range of relationships with friends, colleagues she mentored, and neighbors who provided a satisfying social network, and she continued to contribute to her field via scholarly writing projects. Before the pandemic, she found occasional sessions helpful in putting her health fears into perspective. When the pandemic led her to isolate at home, Ms. A became anxious and depressed to an unprecedented extent. Video sessions were unsatisfying, and she was terrified of taking tranquilizers or other medications. Once COVID-19 vaccinations became available and both she and I received both doses, we switched to meeting in the conference room every 2 to 3 weeks, with considerably better results.

Mr. B, age 41, is a single male who I diagnosed with schizophrenia at age 19 when he developed paranoid delusions and auditory hallucinations. Mr. B was not interested in taking antipsychotic medications, and his situation did not improve even when he did try taking them. He volunteered at a local emergency department doing odd jobs—moving gurneys, cleaning rooms, hauling boxes of supplies—for many years, and had always been employed in jobs such as grocery stocking or janitorial work that did not involve extensive interactions with people. He repeatedly enrolled in programs that would provide a skill such as phlebotomy or medical billing, only to find that he was never hired for such work. We talked once a month for 30 minutes about his frustrations trying to find women to date and marry, and how he was repeatedly taken advantage of (one “date” from an escort service took him to an ATM and got him to withdraw most of the money in his account).

Coincident with COVID-19, Mr. B’s father died from widespread metastatic cancer. His father had been Mr. B’s guide, friend, payee for Social Security Disability Insurance funds, and source of advice. To provide humane and somewhat effective treatment, I saw Mr. B in the conference room. His capacity to express grief and distress at the loss of his father has been impressive, as has his initiative in finding a grief group to attend, which he has done consistently.

Several patients who had been seeing me for weekly psychotherapy chose not to continue, many without specifically informing me of their decision. I understood the situation was in flux, and it would not be clear to anyone what to expect for the future. To avoid pressuring anyone, I chose not to contact patients to inquire about their plans.

Ms. C, age 50, is a professional with 3 children whose marriage had been highly dissatisfying for years, and she was now ready to investigate it. She was very successful in her career, having taken on a leadership role in her firm and earning a high income, while her husband was erratic, unreliable, and self-absorbed. Though he was well-educated and competent in his field, he could not maintain employment in a corporate environment and worked as a consultant with relatively little success. Along with the hours she spent working, Ms. C took responsibility for the family finances, was the chief wage earner, managed the needs of their children, made sure meals were prepared, and took on many other responsibilities.

Continue to: Case examples: How it worked (cont.)...

We agreed to a weekly session that fit Ms. C’s schedule, and she seemed able to relax and talk about herself. I found Ms. C quite likeable and enjoyed meeting with her, though I worried about whether we would need a greater intensity to get at the reasons such a successful and intelligent woman would fear setting limits with her husband or even considering ending the relationship. The reasons were clear as we put together the story of her early life, but conviction only develops with full emotional awareness (transference provides this in psychoanalysis).

The pandemic started approximately 18 months into our work, and Ms. C disappeared. She called my administrative assistant to cancel further appointments but did not ask to speak with me directly. While I knew this might represent resistance, I also felt unwilling to pressure Ms. C if she chose not to continue. I remain hopeful that I will hear from her once again; if not, I will send a note by mail to say that I enjoyed working with her, am happy to see her again, and hope she found some benefit from our work.

Mr. D contacted me for psychotherapy following the death of his father, who I had seen as a patient many years earlier. I was aware of the likely impact of his father’s outsized personality and emotional dysregulation on Mr. D and agreed to meet with him. He had taken over the family business and had made it an even greater success, but had trouble feeling confident about setting limits with employees who he knew took advantage of his avoidance.

Mr. D and I met weekly for several months and then moved to every other week, a form of resistance I expected as we got closer to his feeling pain. At the same time, I recognize that many patients use this tactic to “dose” themselves with the intensity they can tolerate, and Mr. D was quite observant and able to pick up themes where we’d left off.

When the pandemic shut down office visits, Mr. D immediately agreed to video sessions, which he has continued at roughly the same frequency. While I miss sitting with him, we continue to make progress towards his goal of learning to see himself as able to compete with his father.

Psychoanalysis patients 

I found that patients in psychoanalysis had no trouble with the transition to telephone sessions, and the intensity of the work was not diluted. In some ways, audio-only communication is more intimate and might encourage patients to talk about topics they may not have otherwise brought up. I have not seen any evidence of less progress among these patients.

Dr. E, age 45, is a divorced physician who began psychoanalysis 3 times per week on the couch in 2018 for problems with frustration and confusion about his career, his identity as a father, and intense loneliness. He had worked up to 80 hours per week to earn as much money as he could, but also to avoid time at home with his then-wife and young children. The lack of time to recover led him to hate his work, left no time for social connections, and led to binges of heavy drinking. Our work had begun to allow him to develop a narrative about his early life that had never been considered, and to identify patterns of repetition of old defensive strategies that had never served him well.

At the onset of the pandemic, I told Dr. E that we would have to switch to telephone sessions, and he agreed immediately. In fact, he came to prefer telephone work since it spared him the 2 hours per day he had spent coming to my office. While I found it less satisfying than working in person, we have continued the same schedule and with the same intensity and trajectory established before the pandemic.

Continue to: Working with new patients...

Seeing new patients for diagnostic evaluation is always best done in person, because the information I gain from the patient’s appearance, clothing, demeanor, gait, postures, gesturing, and facial expressions (among other elements) gives me important impressions I miss with video or telephone. In many cases, patients gain a sense of who I am from sitting in my office, and using the conference room eliminates that benefit. I attempted to create a warm environment in the conference room by obtaining lamps that produce warmer indirect light and hanging artwork that reflects my tastes. There are clocks in places that allow me and my patient to keep track of time. In meeting new patients by video, I get some impressions about their surroundings that add to the information I get through our interview. I have done many diagnostic evaluations during the pandemic and gotten treatments (whether medication, psychotherapy, or both) underway without discernible problems in the outcomes. Patients who started with me in person have mostly wanted to continue with in-person meetings, but as many have told me, interspersed video sessions save them travel time.

What about vaccination?

Once COVID-19 vaccinations were widely available, I assumed patients would be as eager to get them as I had been. When I began asking patients about whether they had gotten their vaccines, I was surprised to hear that a few were not going to get vaccinated, clearly based on political views and misinformation about the danger of vaccines. (The topic of political beliefs and their impact on psychological treatment is beyond the scope of this commentary.) I tried to counter obvious misinformation, repeated my recommendation that the patient get vaccinated, and then turned to other topics. I later decided to tell all patients that vaccination was required to enter the office. Only 1 patient who had been coming to the office dropped out, and she eventually returned to meeting by video.

COVID-19’s toll on the therapist

While the first several months of the pandemic were so full of uncertainty about the future, once vaccinations were available, it seemed cause for hope of a return to normalcy. As time went on, however, it became clear that normal was still a long way off. With vaccine refusal and new variants upending my naïve view that we were near the end, I began to feel aware of the impact this had on me, and began to focus on self-care (Box). I had always seen myself as unusually lucky to have a full practice, a supportive partnership with my husband, grown children who didn’t need me to homeschool them, a strong social network of friends who could share the burden and cheer each other up at outdoor gatherings, and a wonderful group of siblings and in-laws (all in different cities) who stayed in touch via video calls and quarantined in advance of getting together in someone’s home.

Box

Staying busy and engaged with my practice, spouse, family, and friends kept sadness away most of the time. But I surprised myself a few months ago when I sat down to reflect and check in with myself. I felt enormous loss, resentment, and exhaustion at the privations of the pandemic: every trip to the grocery story felt dangerous. I hadn’t seen the inside of a concert hall, movie theater, restaurant, or museum in nearly 2 years. Travel for meetings and visits to family and friends and various adventures had been abruptly stopped. I lost both parents (not to COVID-19) during 2020; both were older adults living in senior communities that could not allow visitors. The usual grieving process would include attending services at my synagogue where I could say Kaddish for them, and video services were simply not tolerable.

Most of us have become experts at video meetings and likely have come to despise them. While our Institute has always held classes with some out-of-town students joining by video, with a very sophisticated system that provides excellent sound and visual fidelity, teaching entirely by video is another matter. I now teach students I have never met in person and might not recognize if I passed them in public. The art of creating discussion around a table is much more difficult on a computer screen. The first class I taught to residents during the pandemic was completely disorienting as I faced a wall of black screens with names and silence. Each student had turned off their camera and muted their microphone, so I was lecturing to a computer. That never happened again after I insisted on seeing everyone’s face and hearing their voices.

Thankfully, my usual experience of a long day seeing patients followed by chatting while cooking dinner with my husband and walking the dogs before settling down to read didn’t change. But the pleasure of sitting with patients was replaced by the daily grind of figuring out who will need a video link, who will be on the telephone, and who will come to the office, and it doesn’t feel the same. Again, in the big picture, I realize how fortunate I have been, but it’s been a big change in the world of the psychotherapist.

COVID-19 affected all aspects of psychiatric care. As a psychiatrist who is also a psychoanalyst, I faced some unique challenges to caring for my patients during the pandemic. In this article, I describe how COVID-19 impacted my practice, and how I adjusted to ensure that my patients received the best possible care.

The loss of ‘normal’

Our recognition of the loss was not immediate since no one knew what to expect. From March 11, 2020 through the end of the warm weather, when we could be outdoors, personal life was still gratifying. There was even a new spirit of togetherness in my neighborhood, with people seamlessly cooperating by crossing the street to avoid getting too close to one another, practicing proper social distancing in the grocery line, and smiling at everyone.

November 2020 through Spring 2021 was an unprecedented period of no socialization and spending time exclusively with my husband. By the end, I was finally aware of the exhaustion I felt trying to work with patients via phone and video sessions. Beyond that, we were (and still are) conducting administrative meetings and national organization meetings by video.

Spring 2021 until the arrival of cold weather felt more relaxed, as socializing outside again became possible. But from Winter 2021 to now has been a weary repeat of isolation, and a realization that my work life might never go back to “normal.” I would have to make peace with various sorts of losses of gratification in my work.

Life before COVID-19

I am a psychiatrist and psychoanalyst in a group private practice near the University of Cincinnati Medical Center. As a former full-time faculty member there, I maintain some teaching and supervision of residents. I typically see patients from 8:30 AM until 6:30 PM, and for years have had an average of 5 patients in psychoanalysis on the couch for 3 to 4 sessions per week. I see some psychotherapy patients weekly or twice a week and have some hours for new diagnostic evaluations and medication management. In addition, as a faculty member of the Cincinnati Psychoanalytic Institute, I take part in several committees, teach in the psychotherapy program and psychoanalytic training program, and supervise students and candidates. Most weeks, I see between 35 and 40 patients, with 4 to 6 weeks of vacation time per year.

Major changes with the onset of the pandemic

Once the threat from COVID-19 became clear in March 2020, I thought through my options. My office comprises 5 professional offices, a waiting room, and an administrative area. Our administrative assistant and 1 or 2 practitioners were in the office with me most days. We maintained appropriate distance from each another and wore masks in common areas. The practice group was exemplary in immediately setting up safe practices. I learned a few colleagues were seeing patients outside using lawn chairs in the back of our lot where there was some privacy, but many stopped coming to the building altogether.

I felt real sadness having to tell patients I could no longer see them in my office. However, I was relieved to find how quickly many patients made an immediate transition to telephone or video sessions. Since I was alone in my office and not distracted by barking dogs, ringing doorbells, or loud lawnmowers, I continued to come to the office, and never switched to working from home.

Since I was not vis-à-vis with patients on the couch, those sessions shifted to the telephone. I offered psychotherapy patients the option of video sessions via the Health Insurance Portability and Accountability Act–compliant Doximity app (doxy.me) or telephone, and found that approximately 75% preferred video. When I used the telephone, I used a professional-grade headset, which made it less onerous than being tied to a receiver, and I occasionally used the speaker option. I also installed a desk platform that allows me to raise and lower my computer from sitting to standing height.

I worried a great deal about patients I felt would do poorly with video or telephone sessions: older adults who found comfort in human contact that was sometimes curative, less well-integrated individuals who needed real contact in order to feel there was a treatment process, those with serious mental illnesses who needed reassurance at their reality-testing, and new patients who I couldn’t fully assess without in-person meetings.

In the beginning of the pandemic, as we were still learning about the virus, nothing seemed safe. We were washing our hands constantly, afraid to touch doorknobs, mail, or groceries. Thankfully, we learned that COVID-19 transmission occurs primarily through inhalation of droplets and particles containing the virus.¹ Masks, good ventilation, and adequate distance from others considerably cut infection rates. By January 2021, the availability of a vaccine made an enormous difference in vulnerability to severe illness.

When I stopped seeing patients in my office, I set up the conference room that had doors on either end so I could sit on one end of a table and have the patient at the other end, keeping about 8 feet between us. I also kept a fan blowing air away from me and parallel to the patient. After each session, I opened both doors to allow for full ventilation of the room. This provided a solution for the patients I knew I needed to meet with in person.

The following case examples illustrate how I provided care during this time. To protect patient anonymity, these vignettes are composites.

Psychotherapy patients 

Established patients in psychotherapy have seemed to work well with video or telephone sessions. The video option added a new element I never appreciated: seeing patients in their homes or cars allowed me to gain a new set of impressions about them. The use of technology is clearly another element I would not have identified before. Less technically adept older patients are likely to join a video session with only the top of their head visible, or with insufficient lighting. In some cases, I coached patients to rearrange their computer so I could see their faces, but only if it seemed that doing so would not cause them greater distress.

Ms. A, age 74, is a widow who retired from a high-level professional position 5 years ago. She was brought to the hospital due to ongoing anxiety, especially about her health. Ms. A maintained a wide range of relationships with friends, colleagues she mentored, and neighbors who provided a satisfying social network, and she continued to contribute to her field via scholarly writing projects. Before the pandemic, she found occasional sessions helpful in putting her health fears into perspective. When the pandemic led her to isolate at home, Ms. A became anxious and depressed to an unprecedented extent. Video sessions were unsatisfying, and she was terrified of taking tranquilizers or other medications. Once COVID-19 vaccinations became available and both she and I received both doses, we switched to meeting in the conference room every 2 to 3 weeks, with considerably better results.

Mr. B, age 41, is a single male who I diagnosed with schizophrenia at age 19 when he developed paranoid delusions and auditory hallucinations. Mr. B was not interested in taking antipsychotic medications, and his situation did not improve even when he did try taking them. He volunteered at a local emergency department doing odd jobs—moving gurneys, cleaning rooms, hauling boxes of supplies—for many years, and had always been employed in jobs such as grocery stocking or janitorial work that did not involve extensive interactions with people. He repeatedly enrolled in programs that would provide a skill such as phlebotomy or medical billing, only to find that he was never hired for such work. We talked once a month for 30 minutes about his frustrations trying to find women to date and marry, and how he was repeatedly taken advantage of (one “date” from an escort service took him to an ATM and got him to withdraw most of the money in his account).

Coincident with COVID-19, Mr. B’s father died from widespread metastatic cancer. His father had been Mr. B’s guide, friend, payee for Social Security Disability Insurance funds, and source of advice. To provide humane and somewhat effective treatment, I saw Mr. B in the conference room. His capacity to express grief and distress at the loss of his father has been impressive, as has his initiative in finding a grief group to attend, which he has done consistently.

Several patients who had been seeing me for weekly psychotherapy chose not to continue, many without specifically informing me of their decision. I understood the situation was in flux, and it would not be clear to anyone what to expect for the future. To avoid pressuring anyone, I chose not to contact patients to inquire about their plans.

Ms. C, age 50, is a professional with 3 children whose marriage had been highly dissatisfying for years, and she was now ready to investigate it. She was very successful in her career, having taken on a leadership role in her firm and earning a high income, while her husband was erratic, unreliable, and self-absorbed. Though he was well-educated and competent in his field, he could not maintain employment in a corporate environment and worked as a consultant with relatively little success. Along with the hours she spent working, Ms. C took responsibility for the family finances, was the chief wage earner, managed the needs of their children, made sure meals were prepared, and took on many other responsibilities.

Continue to: Case examples: How it worked (cont.)...

We agreed to a weekly session that fit Ms. C’s schedule, and she seemed able to relax and talk about herself. I found Ms. C quite likeable and enjoyed meeting with her, though I worried about whether we would need a greater intensity to get at the reasons such a successful and intelligent woman would fear setting limits with her husband or even considering ending the relationship. The reasons were clear as we put together the story of her early life, but conviction only develops with full emotional awareness (transference provides this in psychoanalysis).

The pandemic started approximately 18 months into our work, and Ms. C disappeared. She called my administrative assistant to cancel further appointments but did not ask to speak with me directly. While I knew this might represent resistance, I also felt unwilling to pressure Ms. C if she chose not to continue. I remain hopeful that I will hear from her once again; if not, I will send a note by mail to say that I enjoyed working with her, am happy to see her again, and hope she found some benefit from our work.

Mr. D contacted me for psychotherapy following the death of his father, who I had seen as a patient many years earlier. I was aware of the likely impact of his father’s outsized personality and emotional dysregulation on Mr. D and agreed to meet with him. He had taken over the family business and had made it an even greater success, but had trouble feeling confident about setting limits with employees who he knew took advantage of his avoidance.

Mr. D and I met weekly for several months and then moved to every other week, a form of resistance I expected as we got closer to his feeling pain. At the same time, I recognize that many patients use this tactic to “dose” themselves with the intensity they can tolerate, and Mr. D was quite observant and able to pick up themes where we’d left off.

When the pandemic shut down office visits, Mr. D immediately agreed to video sessions, which he has continued at roughly the same frequency. While I miss sitting with him, we continue to make progress towards his goal of learning to see himself as able to compete with his father.

Psychoanalysis patients 

I found that patients in psychoanalysis had no trouble with the transition to telephone sessions, and the intensity of the work was not diluted. In some ways, audio-only communication is more intimate and might encourage patients to talk about topics they may not have otherwise brought up. I have not seen any evidence of less progress among these patients.

Dr. E, age 45, is a divorced physician who began psychoanalysis 3 times per week on the couch in 2018 for problems with frustration and confusion about his career, his identity as a father, and intense loneliness. He had worked up to 80 hours per week to earn as much money as he could, but also to avoid time at home with his then-wife and young children. The lack of time to recover led him to hate his work, left no time for social connections, and led to binges of heavy drinking. Our work had begun to allow him to develop a narrative about his early life that had never been considered, and to identify patterns of repetition of old defensive strategies that had never served him well.

At the onset of the pandemic, I told Dr. E that we would have to switch to telephone sessions, and he agreed immediately. In fact, he came to prefer telephone work since it spared him the 2 hours per day he had spent coming to my office. While I found it less satisfying than working in person, we have continued the same schedule and with the same intensity and trajectory established before the pandemic.

Continue to: Working with new patients...

Seeing new patients for diagnostic evaluation is always best done in person, because the information I gain from the patient’s appearance, clothing, demeanor, gait, postures, gesturing, and facial expressions (among other elements) gives me important impressions I miss with video or telephone. In many cases, patients gain a sense of who I am from sitting in my office, and using the conference room eliminates that benefit. I attempted to create a warm environment in the conference room by obtaining lamps that produce warmer indirect light and hanging artwork that reflects my tastes. There are clocks in places that allow me and my patient to keep track of time. In meeting new patients by video, I get some impressions about their surroundings that add to the information I get through our interview. I have done many diagnostic evaluations during the pandemic and gotten treatments (whether medication, psychotherapy, or both) underway without discernible problems in the outcomes. Patients who started with me in person have mostly wanted to continue with in-person meetings, but as many have told me, interspersed video sessions save them travel time.

What about vaccination?

Once COVID-19 vaccinations were widely available, I assumed patients would be as eager to get them as I had been. When I began asking patients about whether they had gotten their vaccines, I was surprised to hear that a few were not going to get vaccinated, clearly based on political views and misinformation about the danger of vaccines. (The topic of political beliefs and their impact on psychological treatment is beyond the scope of this commentary.) I tried to counter obvious misinformation, repeated my recommendation that the patient get vaccinated, and then turned to other topics. I later decided to tell all patients that vaccination was required to enter the office. Only 1 patient who had been coming to the office dropped out, and she eventually returned to meeting by video.

COVID-19’s toll on the therapist

While the first several months of the pandemic were so full of uncertainty about the future, once vaccinations were available, it seemed cause for hope of a return to normalcy. As time went on, however, it became clear that normal was still a long way off. With vaccine refusal and new variants upending my naïve view that we were near the end, I began to feel aware of the impact this had on me, and began to focus on self-care (Box). I had always seen myself as unusually lucky to have a full practice, a supportive partnership with my husband, grown children who didn’t need me to homeschool them, a strong social network of friends who could share the burden and cheer each other up at outdoor gatherings, and a wonderful group of siblings and in-laws (all in different cities) who stayed in touch via video calls and quarantined in advance of getting together in someone’s home.

Box

Staying busy and engaged with my practice, spouse, family, and friends kept sadness away most of the time. But I surprised myself a few months ago when I sat down to reflect and check in with myself. I felt enormous loss, resentment, and exhaustion at the privations of the pandemic: every trip to the grocery story felt dangerous. I hadn’t seen the inside of a concert hall, movie theater, restaurant, or museum in nearly 2 years. Travel for meetings and visits to family and friends and various adventures had been abruptly stopped. I lost both parents (not to COVID-19) during 2020; both were older adults living in senior communities that could not allow visitors. The usual grieving process would include attending services at my synagogue where I could say Kaddish for them, and video services were simply not tolerable.

Most of us have become experts at video meetings and likely have come to despise them. While our Institute has always held classes with some out-of-town students joining by video, with a very sophisticated system that provides excellent sound and visual fidelity, teaching entirely by video is another matter. I now teach students I have never met in person and might not recognize if I passed them in public. The art of creating discussion around a table is much more difficult on a computer screen. The first class I taught to residents during the pandemic was completely disorienting as I faced a wall of black screens with names and silence. Each student had turned off their camera and muted their microphone, so I was lecturing to a computer. That never happened again after I insisted on seeing everyone’s face and hearing their voices.

Thankfully, my usual experience of a long day seeing patients followed by chatting while cooking dinner with my husband and walking the dogs before settling down to read didn’t change. But the pleasure of sitting with patients was replaced by the daily grind of figuring out who will need a video link, who will be on the telephone, and who will come to the office, and it doesn’t feel the same. Again, in the big picture, I realize how fortunate I have been, but it’s been a big change in the world of the psychotherapist.

Evidence is strong that sexual partners transmit microbiota (bacteria, viruses, fungi, protozoa, and archaea) to each other. While microbial flora are abundant in the gastrointestinal tract, they are also present in the vagina, penis, urethra, mouth, and skin.¹ For better or worse, sexual contact of all types means that participants will acquire each other’s microbiota.

The 39 trillion microbiota in the body (which exceed the 30 trillion cells in the body) are commensal and influence both the larger brain in the skull and the smaller enteric brain in the gut. The microbiota and their microbiome genes (1,000 times larger than the human genome) have been linked to depression, anxiety, psychosis, and autism.^2-4 They produce 90% of the body’s serotonin, as well as catecholamines (norepinephrine, epinephrine, dopamine), make hormones (eg, cortisol), and modulate the immune system. Microbiota have several important functions, including food digestion, synthesis of vitamins, autoimmunity, hypothalamic-pituitary-adrenal axis regulation, and CNS modulation.

Consequences of dysbiosis

Everyone should be concerned about maintaining a healthy diversity of microbiota in their body, with a predominance of beneficial bacteria such as Lactobacillus and Bacteroides, and avoiding acquiring pathogenic bacteria such as Gardnerella, Prevotella, and Atopobium. Sexual activity involving a partner with unhealthy microbiota may increase the risk of dysbiosis, defined as a reduction in microbiota diversity, including a loss of beneficial bacteria and a rise in harmful bacteria.

Dysbiosis is associated with multiple symptoms, including⁵:

• brain “fog,” irritability, mood changes, and anxiety
• bloating, loss of intestinal permeability, and insufficient reclamation of nutrients
• congestion of certain organs, such as the liver, gallbladder, and pancreas
• production of antigen-antibody complexes in response to chemicals in partially digested food
• aggravation of inflammatory disorders such as migraine, arthritis, and autoimmune disorders.

Apart from intimate sexual contact, simply sharing a household with someone leads to sharing of gut microflora. Persons who live together, whether genetically related or not, have similar microbiota. Compared with people living in separate households, cohabiting human pairs, dog pairs, and human-dog pairs share most of their microbiota (especially in the skin).

A consequence of acquiring pathogenic microbiota in the vagina is bacterial vaginosis (BV), which is not an infection but an ecologic imbalance in the composition of the vaginal microbiota. BV is caused by a significant decline in the beneficial vaginal Lactobacillus and a marked increase in the non-Lactobacillus taxa (especially Gardnerella and Atopobium).⁶ It can last for a least 1 week after sexual intercourse. BV is rare or absent among virgins. For a male partner, penile microbiota changes significantly after unprotected sex.⁶

Pathogenic bacteria can be cultivated from the glans, the coronal sulcus, and the prepuce, as well as from the penile skin, semen, urethra, and urine.⁶ Diverse bacteria exist in human semen, regardless if the male is fertile or infertile.⁷Anaerococcus is a biomarker for low sperm quality. Many of the semen bacteria are also found in the vagina of women with BV.⁷ Semen is a medium for the transmission of bacteria and viruses between men and women, and can contribute to sexually transmitted diseases.⁸

There are approximately 21 million cases of BV in the United States each year, and BV can also increase the risk of HIV and poor obstetric outcomes.⁹ The microbiota in the penile skin and urethra in males who have monogamous relationships with females are very similar to the vaginal microbiota of their female partner.

Consequences of BV include:

• decrease in hydrogen peroxide–producing bacilli
• prevalence of anaerobic bacteria (Prevotella, Gardnerella, and Atopobium)
• alkalinization, fishy odor, and gray-white vaginal discharge
• increase in the rate of pelvic inflammatory disease, ectopic pregnancy, endometriosis, preterm birth, and tubal factor infertility.⁹

Circumcision decreases the risk of BV. There is an increased rate of BV bacterial taxa in men with extramarital affairs and in women with multiple partners. Both oral and vaginal sex increase the abundance of Lactobacillus in the male oral and penile microbiota. Gingivitis has also been reported after oral sex.¹⁰

A link to psychiatric disorders

Given that all forms of sexual contact (vaginal, oral, anal, or skin) can transmit microbiota bidirectionally between partners, it is vital to practice safe sex and consider a monogamous relationship rather than indiscriminate promiscuity. Unfortunately, certain psychiatric disorders, such as bipolar disorder, are associated with hypersexuality and multiple partners, which may disrupt the microbiota. This can further disrupt the diversity of an individual’s microbiome and may put them at risk for mood, anxiety, and other psychiatric disorders. Another problem is sexually transmitted infections such as gonorrhea or syphilis require antibiotic therapy. It is well established that antibiotics kill both the bad pathogenic and the good nonpathogenic microbiota, further exacerbating dysbiosis and leading to disruptions in the microbiota-gut-brain (MGB) axis, which then results in psychiatric disorders.

The MGB axis modulates neurological processes via the vagus nerve, the major “highway” connecting the gut and brain for bidirectional traffic. The MGB axis produces microbial metabolites and immune factors that can lead to changes in brain neurotransmitters as well as neuroinflammation and psychiatric symptoms such as depression and anxiety.⁵

Many researchers are focusing on how to exploit the microbiome to develop novel therapeutic strategies, and encouraging advances are emerging.⁵ But the exact mechanisms by which the gut microbiome can impact mental health is still a work in progress. It is highly likely that dysbiosis is associated with mood and anxiety symptoms.

The bottom line: Sexual activity—whether it is heavy kissing, vaginal intercourse, oral sex, anal sex, or extensive skin contact—can lead to the exchange of microbiota. If an individual has dysbiosis, that could impact the mental health of their sexual partner(s). This raises the question of whether counseling patients about avoiding indiscriminate sex and practicing safe sex is as important for mental health as diet and exercise counseling is for physical health.

Evidence is strong that sexual partners transmit microbiota (bacteria, viruses, fungi, protozoa, and archaea) to each other. While microbial flora are abundant in the gastrointestinal tract, they are also present in the vagina, penis, urethra, mouth, and skin.¹ For better or worse, sexual contact of all types means that participants will acquire each other’s microbiota.

The 39 trillion microbiota in the body (which exceed the 30 trillion cells in the body) are commensal and influence both the larger brain in the skull and the smaller enteric brain in the gut. The microbiota and their microbiome genes (1,000 times larger than the human genome) have been linked to depression, anxiety, psychosis, and autism.^2-4 They produce 90% of the body’s serotonin, as well as catecholamines (norepinephrine, epinephrine, dopamine), make hormones (eg, cortisol), and modulate the immune system. Microbiota have several important functions, including food digestion, synthesis of vitamins, autoimmunity, hypothalamic-pituitary-adrenal axis regulation, and CNS modulation.

Consequences of dysbiosis

Everyone should be concerned about maintaining a healthy diversity of microbiota in their body, with a predominance of beneficial bacteria such as Lactobacillus and Bacteroides, and avoiding acquiring pathogenic bacteria such as Gardnerella, Prevotella, and Atopobium. Sexual activity involving a partner with unhealthy microbiota may increase the risk of dysbiosis, defined as a reduction in microbiota diversity, including a loss of beneficial bacteria and a rise in harmful bacteria.

Dysbiosis is associated with multiple symptoms, including⁵:

• brain “fog,” irritability, mood changes, and anxiety
• bloating, loss of intestinal permeability, and insufficient reclamation of nutrients
• congestion of certain organs, such as the liver, gallbladder, and pancreas
• production of antigen-antibody complexes in response to chemicals in partially digested food
• aggravation of inflammatory disorders such as migraine, arthritis, and autoimmune disorders.

Apart from intimate sexual contact, simply sharing a household with someone leads to sharing of gut microflora. Persons who live together, whether genetically related or not, have similar microbiota. Compared with people living in separate households, cohabiting human pairs, dog pairs, and human-dog pairs share most of their microbiota (especially in the skin).

A consequence of acquiring pathogenic microbiota in the vagina is bacterial vaginosis (BV), which is not an infection but an ecologic imbalance in the composition of the vaginal microbiota. BV is caused by a significant decline in the beneficial vaginal Lactobacillus and a marked increase in the non-Lactobacillus taxa (especially Gardnerella and Atopobium).⁶ It can last for a least 1 week after sexual intercourse. BV is rare or absent among virgins. For a male partner, penile microbiota changes significantly after unprotected sex.⁶

Pathogenic bacteria can be cultivated from the glans, the coronal sulcus, and the prepuce, as well as from the penile skin, semen, urethra, and urine.⁶ Diverse bacteria exist in human semen, regardless if the male is fertile or infertile.⁷Anaerococcus is a biomarker for low sperm quality. Many of the semen bacteria are also found in the vagina of women with BV.⁷ Semen is a medium for the transmission of bacteria and viruses between men and women, and can contribute to sexually transmitted diseases.⁸

There are approximately 21 million cases of BV in the United States each year, and BV can also increase the risk of HIV and poor obstetric outcomes.⁹ The microbiota in the penile skin and urethra in males who have monogamous relationships with females are very similar to the vaginal microbiota of their female partner.

Consequences of BV include:

• decrease in hydrogen peroxide–producing bacilli
• prevalence of anaerobic bacteria (Prevotella, Gardnerella, and Atopobium)
• alkalinization, fishy odor, and gray-white vaginal discharge
• increase in the rate of pelvic inflammatory disease, ectopic pregnancy, endometriosis, preterm birth, and tubal factor infertility.⁹

Circumcision decreases the risk of BV. There is an increased rate of BV bacterial taxa in men with extramarital affairs and in women with multiple partners. Both oral and vaginal sex increase the abundance of Lactobacillus in the male oral and penile microbiota. Gingivitis has also been reported after oral sex.¹⁰

A link to psychiatric disorders

Given that all forms of sexual contact (vaginal, oral, anal, or skin) can transmit microbiota bidirectionally between partners, it is vital to practice safe sex and consider a monogamous relationship rather than indiscriminate promiscuity. Unfortunately, certain psychiatric disorders, such as bipolar disorder, are associated with hypersexuality and multiple partners, which may disrupt the microbiota. This can further disrupt the diversity of an individual’s microbiome and may put them at risk for mood, anxiety, and other psychiatric disorders. Another problem is sexually transmitted infections such as gonorrhea or syphilis require antibiotic therapy. It is well established that antibiotics kill both the bad pathogenic and the good nonpathogenic microbiota, further exacerbating dysbiosis and leading to disruptions in the microbiota-gut-brain (MGB) axis, which then results in psychiatric disorders.

The MGB axis modulates neurological processes via the vagus nerve, the major “highway” connecting the gut and brain for bidirectional traffic. The MGB axis produces microbial metabolites and immune factors that can lead to changes in brain neurotransmitters as well as neuroinflammation and psychiatric symptoms such as depression and anxiety.⁵

Many researchers are focusing on how to exploit the microbiome to develop novel therapeutic strategies, and encouraging advances are emerging.⁵ But the exact mechanisms by which the gut microbiome can impact mental health is still a work in progress. It is highly likely that dysbiosis is associated with mood and anxiety symptoms.

The bottom line: Sexual activity—whether it is heavy kissing, vaginal intercourse, oral sex, anal sex, or extensive skin contact—can lead to the exchange of microbiota. If an individual has dysbiosis, that could impact the mental health of their sexual partner(s). This raises the question of whether counseling patients about avoiding indiscriminate sex and practicing safe sex is as important for mental health as diet and exercise counseling is for physical health.

Evidence is strong that sexual partners transmit microbiota (bacteria, viruses, fungi, protozoa, and archaea) to each other. While microbial flora are abundant in the gastrointestinal tract, they are also present in the vagina, penis, urethra, mouth, and skin.¹ For better or worse, sexual contact of all types means that participants will acquire each other’s microbiota.

The 39 trillion microbiota in the body (which exceed the 30 trillion cells in the body) are commensal and influence both the larger brain in the skull and the smaller enteric brain in the gut. The microbiota and their microbiome genes (1,000 times larger than the human genome) have been linked to depression, anxiety, psychosis, and autism.^2-4 They produce 90% of the body’s serotonin, as well as catecholamines (norepinephrine, epinephrine, dopamine), make hormones (eg, cortisol), and modulate the immune system. Microbiota have several important functions, including food digestion, synthesis of vitamins, autoimmunity, hypothalamic-pituitary-adrenal axis regulation, and CNS modulation.

Consequences of dysbiosis

Everyone should be concerned about maintaining a healthy diversity of microbiota in their body, with a predominance of beneficial bacteria such as Lactobacillus and Bacteroides, and avoiding acquiring pathogenic bacteria such as Gardnerella, Prevotella, and Atopobium. Sexual activity involving a partner with unhealthy microbiota may increase the risk of dysbiosis, defined as a reduction in microbiota diversity, including a loss of beneficial bacteria and a rise in harmful bacteria.

Dysbiosis is associated with multiple symptoms, including⁵:

• brain “fog,” irritability, mood changes, and anxiety
• bloating, loss of intestinal permeability, and insufficient reclamation of nutrients
• congestion of certain organs, such as the liver, gallbladder, and pancreas
• production of antigen-antibody complexes in response to chemicals in partially digested food
• aggravation of inflammatory disorders such as migraine, arthritis, and autoimmune disorders.

Apart from intimate sexual contact, simply sharing a household with someone leads to sharing of gut microflora. Persons who live together, whether genetically related or not, have similar microbiota. Compared with people living in separate households, cohabiting human pairs, dog pairs, and human-dog pairs share most of their microbiota (especially in the skin).

A consequence of acquiring pathogenic microbiota in the vagina is bacterial vaginosis (BV), which is not an infection but an ecologic imbalance in the composition of the vaginal microbiota. BV is caused by a significant decline in the beneficial vaginal Lactobacillus and a marked increase in the non-Lactobacillus taxa (especially Gardnerella and Atopobium).⁶ It can last for a least 1 week after sexual intercourse. BV is rare or absent among virgins. For a male partner, penile microbiota changes significantly after unprotected sex.⁶

Pathogenic bacteria can be cultivated from the glans, the coronal sulcus, and the prepuce, as well as from the penile skin, semen, urethra, and urine.⁶ Diverse bacteria exist in human semen, regardless if the male is fertile or infertile.⁷Anaerococcus is a biomarker for low sperm quality. Many of the semen bacteria are also found in the vagina of women with BV.⁷ Semen is a medium for the transmission of bacteria and viruses between men and women, and can contribute to sexually transmitted diseases.⁸

There are approximately 21 million cases of BV in the United States each year, and BV can also increase the risk of HIV and poor obstetric outcomes.⁹ The microbiota in the penile skin and urethra in males who have monogamous relationships with females are very similar to the vaginal microbiota of their female partner.

Consequences of BV include:

• decrease in hydrogen peroxide–producing bacilli
• prevalence of anaerobic bacteria (Prevotella, Gardnerella, and Atopobium)
• alkalinization, fishy odor, and gray-white vaginal discharge
• increase in the rate of pelvic inflammatory disease, ectopic pregnancy, endometriosis, preterm birth, and tubal factor infertility.⁹

Circumcision decreases the risk of BV. There is an increased rate of BV bacterial taxa in men with extramarital affairs and in women with multiple partners. Both oral and vaginal sex increase the abundance of Lactobacillus in the male oral and penile microbiota. Gingivitis has also been reported after oral sex.¹⁰

A link to psychiatric disorders

Given that all forms of sexual contact (vaginal, oral, anal, or skin) can transmit microbiota bidirectionally between partners, it is vital to practice safe sex and consider a monogamous relationship rather than indiscriminate promiscuity. Unfortunately, certain psychiatric disorders, such as bipolar disorder, are associated with hypersexuality and multiple partners, which may disrupt the microbiota. This can further disrupt the diversity of an individual’s microbiome and may put them at risk for mood, anxiety, and other psychiatric disorders. Another problem is sexually transmitted infections such as gonorrhea or syphilis require antibiotic therapy. It is well established that antibiotics kill both the bad pathogenic and the good nonpathogenic microbiota, further exacerbating dysbiosis and leading to disruptions in the microbiota-gut-brain (MGB) axis, which then results in psychiatric disorders.

The MGB axis modulates neurological processes via the vagus nerve, the major “highway” connecting the gut and brain for bidirectional traffic. The MGB axis produces microbial metabolites and immune factors that can lead to changes in brain neurotransmitters as well as neuroinflammation and psychiatric symptoms such as depression and anxiety.⁵

Many researchers are focusing on how to exploit the microbiome to develop novel therapeutic strategies, and encouraging advances are emerging.⁵ But the exact mechanisms by which the gut microbiome can impact mental health is still a work in progress. It is highly likely that dysbiosis is associated with mood and anxiety symptoms.

The bottom line: Sexual activity—whether it is heavy kissing, vaginal intercourse, oral sex, anal sex, or extensive skin contact—can lead to the exchange of microbiota. If an individual has dysbiosis, that could impact the mental health of their sexual partner(s). This raises the question of whether counseling patients about avoiding indiscriminate sex and practicing safe sex is as important for mental health as diet and exercise counseling is for physical health.

Mr. B, age 64, is being treated in the psychiatric clinic for generalized anxiety disorder. He also has a history of type 2 diabetes mellitus and osteoarthritis. His present medications include metformin 500 mg twice daily, escitalopram 20 mg/d, and a multivitamin.

Three months after a shingles outbreak on his left trunk, Mr. B develops a sharp, burning pain and hypersensitivity to light in the same area as the shingles flare-up. He is diagnosed with postherpetic neuralgia. Despite a 12-week trial of cognitive-behavioral therapy, Mr. B continues to report excessive worry, irritability, poor concentration, psycho­motor restlessness, and poor sleep.

Contrasting with the serendipitous discovery of iproniazid and chlorpromazine leading to the development of the current spectrum of antidepressant and antipsychotic agents, discovery of the benefits various antiepileptic agents have in bipolar disorder has not led to a similar proliferation of medication development for bipolar mania or depression.^1-3 Divalproex, one of the most commonly used antiepileptic drugs (AEDs) in psychiatry, was thought to be an inactive organic solvent until it was used in 1962 to test the anticonvulsant activity of other compounds. This led to the discovery and subsequent use of divalproex in patients with epilepsy, followed by FDA approval in bipolar disorder.^4,5 Off-label use of many AEDs as mood-stabilizing agents in bipolar disorder led to the emergence of carbamazepine, divalproex, and lamotrigine, which joined lithium as classic mood-stabilizing agents.^4,6-8 Amid varying definitions of “mood stabilizer,” many AEDs have failed to demonstrate mood-stabilizing effects in bipolar disorder and therefore should not all be considered mood stabilizers.⁹ Nonetheless, the dual use of a single AED for both psychiatric and nonpsychiatric indications can decrease polypharmacy and increase acceptability of medications in patients who have low insight into their illness.^10,11

Because AEDs were originally purposed to treat neurologic disease, psychiatric indications must first be established before considering other indications. AEDs as a class have broad pharmacologic actions, but are generally CNS depressants, decreasing brain signaling through mechanisms such as ion channel antagonism (carbamazepine, gabapentin) or alterations to gamma-aminobutyric acid/glutamate signaling (divalproex, topiramate).^4,6,12,13 Compared to antidepressants and antipsychotics, whose primary use for psychiatric conditions is firmly rooted in evidence, rational use of AEDs for psychiatric conditions and symptoms depends on the agent-specific efficacy. Patients with comorbid psychiatric and neurologic disorders are ideal candidates for dually indicated AEDs due to these agents’ class effects rooted in epilepsy. Due to the history of positive psychiatric benefits with AEDs, newer agents may be psychiatrically beneficial but will likely follow the discovery of these benefits in patients for whom epilepsy is the primary diagnosis.

Consider the limitations

Using AEDs to reduce polypharmacy should be done judiciously from a drug-drug interaction perspective, because certain AEDs (eg, carbamazepine, divalproex) can greatly influence the metabolism of other medications, which may defeat the best intentions of the original intervention.^4,6

Several other limitations should be considered. This article does not include all AEDs, only those commonly used for psychiatric indications with known nonpsychiatric benefits. Some may worsen psychiatric conditions (such as rage and irritability in the case of levetiracetam), and all AEDs have an FDA warning regarding suicidal behaviors and ideation.^14,15 Another important limitation is the potential for differential dosing across indications; tolerability concerns may limit adequate dosing across multiple uses. For example, topiramate’s migraine prophylaxis effect can be achieved at much lower doses than the patient-specific efficacy dosing seen in binge eating disorder, with higher doses increasing the propensity for adverse effects.^13,16Dual-use AEDs should be considered wherever possible, but judicious review of evidence is necessary to appropriately adjudicate a specific patient’s risk vs benefit. The Table^{4,6-9,12,13,16-68}  provides information on select AEDs with both psychiatric and nonpsychiatric indications, including both FDA-approved and common off-label uses. These indications are limited to adult use only.

CASE CONTINUED

After reviewing Mr. B’s medical history, the treating medical team decides to cross-taper escitalopram to duloxetine 30 mg twice daily. Though his pain lessens after several weeks, it persists enough to interfere with Mr. B’s daily life. In addition to duloxetine, he is started on pregabalin 50 mg 3 times a day. Mr. B’s pain decreases to a tolerable level, and he reports decreased worrying and restlessness, and improvements in concentration and sleep.

Mr. B, age 64, is being treated in the psychiatric clinic for generalized anxiety disorder. He also has a history of type 2 diabetes mellitus and osteoarthritis. His present medications include metformin 500 mg twice daily, escitalopram 20 mg/d, and a multivitamin.

Three months after a shingles outbreak on his left trunk, Mr. B develops a sharp, burning pain and hypersensitivity to light in the same area as the shingles flare-up. He is diagnosed with postherpetic neuralgia. Despite a 12-week trial of cognitive-behavioral therapy, Mr. B continues to report excessive worry, irritability, poor concentration, psycho­motor restlessness, and poor sleep.

Contrasting with the serendipitous discovery of iproniazid and chlorpromazine leading to the development of the current spectrum of antidepressant and antipsychotic agents, discovery of the benefits various antiepileptic agents have in bipolar disorder has not led to a similar proliferation of medication development for bipolar mania or depression.^1-3 Divalproex, one of the most commonly used antiepileptic drugs (AEDs) in psychiatry, was thought to be an inactive organic solvent until it was used in 1962 to test the anticonvulsant activity of other compounds. This led to the discovery and subsequent use of divalproex in patients with epilepsy, followed by FDA approval in bipolar disorder.^4,5 Off-label use of many AEDs as mood-stabilizing agents in bipolar disorder led to the emergence of carbamazepine, divalproex, and lamotrigine, which joined lithium as classic mood-stabilizing agents.^4,6-8 Amid varying definitions of “mood stabilizer,” many AEDs have failed to demonstrate mood-stabilizing effects in bipolar disorder and therefore should not all be considered mood stabilizers.⁹ Nonetheless, the dual use of a single AED for both psychiatric and nonpsychiatric indications can decrease polypharmacy and increase acceptability of medications in patients who have low insight into their illness.^10,11

Because AEDs were originally purposed to treat neurologic disease, psychiatric indications must first be established before considering other indications. AEDs as a class have broad pharmacologic actions, but are generally CNS depressants, decreasing brain signaling through mechanisms such as ion channel antagonism (carbamazepine, gabapentin) or alterations to gamma-aminobutyric acid/glutamate signaling (divalproex, topiramate).^4,6,12,13 Compared to antidepressants and antipsychotics, whose primary use for psychiatric conditions is firmly rooted in evidence, rational use of AEDs for psychiatric conditions and symptoms depends on the agent-specific efficacy. Patients with comorbid psychiatric and neurologic disorders are ideal candidates for dually indicated AEDs due to these agents’ class effects rooted in epilepsy. Due to the history of positive psychiatric benefits with AEDs, newer agents may be psychiatrically beneficial but will likely follow the discovery of these benefits in patients for whom epilepsy is the primary diagnosis.

Consider the limitations

Using AEDs to reduce polypharmacy should be done judiciously from a drug-drug interaction perspective, because certain AEDs (eg, carbamazepine, divalproex) can greatly influence the metabolism of other medications, which may defeat the best intentions of the original intervention.^4,6

Several other limitations should be considered. This article does not include all AEDs, only those commonly used for psychiatric indications with known nonpsychiatric benefits. Some may worsen psychiatric conditions (such as rage and irritability in the case of levetiracetam), and all AEDs have an FDA warning regarding suicidal behaviors and ideation.^14,15 Another important limitation is the potential for differential dosing across indications; tolerability concerns may limit adequate dosing across multiple uses. For example, topiramate’s migraine prophylaxis effect can be achieved at much lower doses than the patient-specific efficacy dosing seen in binge eating disorder, with higher doses increasing the propensity for adverse effects.^13,16Dual-use AEDs should be considered wherever possible, but judicious review of evidence is necessary to appropriately adjudicate a specific patient’s risk vs benefit. The Table^{4,6-9,12,13,16-68}  provides information on select AEDs with both psychiatric and nonpsychiatric indications, including both FDA-approved and common off-label uses. These indications are limited to adult use only.

CASE CONTINUED

After reviewing Mr. B’s medical history, the treating medical team decides to cross-taper escitalopram to duloxetine 30 mg twice daily. Though his pain lessens after several weeks, it persists enough to interfere with Mr. B’s daily life. In addition to duloxetine, he is started on pregabalin 50 mg 3 times a day. Mr. B’s pain decreases to a tolerable level, and he reports decreased worrying and restlessness, and improvements in concentration and sleep.

Mr. B, age 64, is being treated in the psychiatric clinic for generalized anxiety disorder. He also has a history of type 2 diabetes mellitus and osteoarthritis. His present medications include metformin 500 mg twice daily, escitalopram 20 mg/d, and a multivitamin.

Three months after a shingles outbreak on his left trunk, Mr. B develops a sharp, burning pain and hypersensitivity to light in the same area as the shingles flare-up. He is diagnosed with postherpetic neuralgia. Despite a 12-week trial of cognitive-behavioral therapy, Mr. B continues to report excessive worry, irritability, poor concentration, psycho­motor restlessness, and poor sleep.

Contrasting with the serendipitous discovery of iproniazid and chlorpromazine leading to the development of the current spectrum of antidepressant and antipsychotic agents, discovery of the benefits various antiepileptic agents have in bipolar disorder has not led to a similar proliferation of medication development for bipolar mania or depression.^1-3 Divalproex, one of the most commonly used antiepileptic drugs (AEDs) in psychiatry, was thought to be an inactive organic solvent until it was used in 1962 to test the anticonvulsant activity of other compounds. This led to the discovery and subsequent use of divalproex in patients with epilepsy, followed by FDA approval in bipolar disorder.^4,5 Off-label use of many AEDs as mood-stabilizing agents in bipolar disorder led to the emergence of carbamazepine, divalproex, and lamotrigine, which joined lithium as classic mood-stabilizing agents.^4,6-8 Amid varying definitions of “mood stabilizer,” many AEDs have failed to demonstrate mood-stabilizing effects in bipolar disorder and therefore should not all be considered mood stabilizers.⁹ Nonetheless, the dual use of a single AED for both psychiatric and nonpsychiatric indications can decrease polypharmacy and increase acceptability of medications in patients who have low insight into their illness.^10,11

Because AEDs were originally purposed to treat neurologic disease, psychiatric indications must first be established before considering other indications. AEDs as a class have broad pharmacologic actions, but are generally CNS depressants, decreasing brain signaling through mechanisms such as ion channel antagonism (carbamazepine, gabapentin) or alterations to gamma-aminobutyric acid/glutamate signaling (divalproex, topiramate).^4,6,12,13 Compared to antidepressants and antipsychotics, whose primary use for psychiatric conditions is firmly rooted in evidence, rational use of AEDs for psychiatric conditions and symptoms depends on the agent-specific efficacy. Patients with comorbid psychiatric and neurologic disorders are ideal candidates for dually indicated AEDs due to these agents’ class effects rooted in epilepsy. Due to the history of positive psychiatric benefits with AEDs, newer agents may be psychiatrically beneficial but will likely follow the discovery of these benefits in patients for whom epilepsy is the primary diagnosis.

Consider the limitations

Using AEDs to reduce polypharmacy should be done judiciously from a drug-drug interaction perspective, because certain AEDs (eg, carbamazepine, divalproex) can greatly influence the metabolism of other medications, which may defeat the best intentions of the original intervention.^4,6

Several other limitations should be considered. This article does not include all AEDs, only those commonly used for psychiatric indications with known nonpsychiatric benefits. Some may worsen psychiatric conditions (such as rage and irritability in the case of levetiracetam), and all AEDs have an FDA warning regarding suicidal behaviors and ideation.^14,15 Another important limitation is the potential for differential dosing across indications; tolerability concerns may limit adequate dosing across multiple uses. For example, topiramate’s migraine prophylaxis effect can be achieved at much lower doses than the patient-specific efficacy dosing seen in binge eating disorder, with higher doses increasing the propensity for adverse effects.^13,16Dual-use AEDs should be considered wherever possible, but judicious review of evidence is necessary to appropriately adjudicate a specific patient’s risk vs benefit. The Table^{4,6-9,12,13,16-68}  provides information on select AEDs with both psychiatric and nonpsychiatric indications, including both FDA-approved and common off-label uses. These indications are limited to adult use only.

CASE CONTINUED

After reviewing Mr. B’s medical history, the treating medical team decides to cross-taper escitalopram to duloxetine 30 mg twice daily. Though his pain lessens after several weeks, it persists enough to interfere with Mr. B’s daily life. In addition to duloxetine, he is started on pregabalin 50 mg 3 times a day. Mr. B’s pain decreases to a tolerable level, and he reports decreased worrying and restlessness, and improvements in concentration and sleep.

Obsessive-compulsive disorder (OCD) is a chronic, debilitating neuropsychiatric disorder that affects 1% to 3% of the population worldwide.^1,2 Together, serotonin reuptake inhibitors (SRIs) and cognitive-behavior therapy (CBT) are considered the first-line treatment for OCD.³ In children and adults, CBT is considered at least as effective as pharmacotherapy.⁴ Despite being an effective treatment, CBT continues to have barriers to its widespread use, including limited availability of trained CBT therapists, delayed clinical response, and high costs.⁵

Only approximately one-half of patients with OCD respond to SRI therapy, and a considerable percentage (30% to 40%) show significant residual symptoms even after multiple trials of SRIs.^6-8 In addition, SRIs may have adverse effects (eg, sexual dysfunction, gastrointestinal symptoms) that impair patient adherence to these medications.⁹ Therefore, finding better treatment options is important for managing patients with OCD.

Augmentation strategies are recommended for patients who show partial response to SRI treatment or poor response to multiple SRIs. Augmentation typically includes incorporating additional medications with the primary drug with the goal of boosting the therapeutic efficacy of the primary drug. Typically, these additional medications have different mechanisms of action. However, there are no large-scale randomized controlled trials (RCTs) to inform treatment augmentation after first-line treatments for OCD produce suboptimal outcomes. The available evidence is predominantly based on small-scale RCTs, open-label trials, and case series.

In this article, we review the evidence for treatment augmentation strategies for OCD and summarize 8 studies that show promising results (Table^10-17). We focus only on pharmacologic agents and do not include other biological interventions, such as repetitive transcranial magnetic stimulation over supplementary motor area, ablative neurosurgery, or deep brain stimulation.

Continue to: Reference 1...

Numerous studies support the role of glutamate dysregulation in the pathophysiology of OCD. Cortico-striato-thalamo-cortical (CSTC) abnormalities play a major role in the pathophysiology of OCD as suggested by neuroimaging research studies that indicate glutamate is the fundamental neurotransmitter of the CSTC circuit. Dysregulation of glutamatergic signaling within this circuit has been linked to OCD. Patients with OCD have been found to have an increase of glutamate in the CSF. As a result, medications that affect glutamate levels can be used to treat patients with OCD who do not respond to first-line agents. In patients already taking SRIs, augmentation of glutamate-modulating medications can reduce OCD symptoms. As an uncompetitive antagonist of the N-methyl-d-aspartate (NMDA)-type glutamate receptor, amantadine has been proposed as 1 of these medications.

Naderi et al¹⁰ evaluated amantadine as augmentative therapy to fluvoxamine for treating patients with moderate to severe OCD.

Study design

• This 12-week, randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of amantadine as an augmentative agent to fluvoxamine in 106 patients age 18 to 60 with moderate to severe OCD.
• Participants met DSM-5 criteria for OCD and had a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score >21. Participants were excluded if they had any substance dependence; an IQ <70; any other Axis I mental disorder; any serious cardiac, renal, or hepatic disease; had received psychotropic medications during the last 6 weeks, were pregnant or breastfeeding, or had rising liver transaminases to 3 times the upper limit of normal or higher.
• Participants received fluvoxamine 100 mg twice daily plus amantadine 100 mg/d, or fluvoxamine 100 mg twice daily plus placebo. All patients received fluvoxamine 100 mg/d for 28 days followed by 200 mg/d for the remainder of the trial.
• The primary outcome measure was difference in Y-BOCS total scores between the amantadine and placebo groups. The secondary outcome was the difference in Y-BOCS obsession and compulsion subscale scores.

Outcomes

• Patients who received amantadine augmentation experienced a significant reduction in Y-BOCS total score (P < .001) and obsession subscale score (P < .01).
• The amantadine group showed good tolerability and safety. There were no clinically significant adverse effects.

• Amantadine is an effective adjuvant to fluvoxamine for reducing OCD symptoms.

Conclusion

• Ondansetron and granisetron can be beneficial as an augmentation strategy for patients with treatment-resistant OCD.

2. Sharafkhah M, Aghakarim Alamdar M, Massoudifar A, et al. Comparing the efficacy of ondansetron and granisetron augmentation in treatment-resistant obsessive-compulsive disorder: a randomized double-blind placebo-controlled study. Int Clin Psychopharmacol. 2019;34(5):222- 233. doi:10.1097/YIC.0000000000000267

Although selective serotonin reuptake inhibitors (SSRIs) are considered a first-line treatment when teamed with CBT and antipsychotic augmentation, symptom resolution is not always achieved, and treatment resistance is a common problem. Sharafkhah et al¹¹ compared the efficacy of ondansetron and granisetron augmentation specifically for patients with treatment-resistant OCD.

Study Design

• In this 18-week, randomized, double-blind, placebo-controlled study, 135 patients with treatment-resistant OCD who were previously treated with a combination of an SSRI and an antipsychotic received augmentation with ondansetron (n = 45, 4 mg/d), granisetron (n = 45, 2 mg/d), or placebo.
• Patients were rated using Y-BOCS every 2 weeks during phase I (intervention period), which lasted 14 weeks. After completing the intervention, patients were followed for 4 more weeks during phase II (discontinuation period).
• The aim of this study was to determine the safety, efficacy, and tolerability of ondansetron vs granisetron as augmentation for patients with treatment-resistant OCD. A secondary aim was to determine the rate of relapse of OCD symptoms after discontinuing ondansetron as compared with granisetron at 4 weeks after intervention.

Outcomes

• At Week 14, the reductions in Y-BOCS scores in the ondansetron, granisetron, and placebo groups were 41.5%, 39.7%, and 15.2%, respectively (P = .001). The reduction in Y-BOCS score in the ondansetron and granisetron groups was significantly greater than placebo at all phase I visits.
• Complete response was higher in the ondansetron group compared with the granisetron group (P = .041).
• Y-BOCS scores increased in both the ondansetron and granisetron groups during the discontinuation phase, but OCD symptoms were not significantly exacerbated.

Conclusion

• Ondansetron and granisetron can be beneficial as an augmentation strategy for patients with treatment-resistant OCD.

3. Modarresi A, Sayyah M, Razooghi S, et al. Memantine augmentation improves symptoms in serotonin reuptake inhibitorrefractory obsessive-compulsive disorder: a randomized controlled trial. Pharmacopsychiatry. 2018;51(6):263-269. doi:10.1055/s-0043-120268

Increased glutamate levels in CSF, glutamatergic overactivity, and polymorphisms of genes coding the NMDA receptor have been shown to contribute to the occurrence of OCD. Memantine is a noncompetitive antagonist of the NMDA receptor. Various control trials have shown augmentation with memantine 5 mg/d to 20 mg/d significantly reduced symptom severity in patients with moderate to severe OCD. Modarresi et al¹² evaluated memantine as a treatment option for patients with severe OCD who did not respond to SRI monotherapy.

Study design

• This 12-week, double-blind, randomized, placebo-controlled trial evaluated the efficacy of memantine augmentation in 32 patients age 18 to 40 who met DSM-5 criteria for OCD, had a Y-BOCS score ≥24, and no psychiatric comorbidity. Participants had not responded to ≥3 adequate trials (minimum 3 months) of SRI therapy, 1 of which was clomipramine.
• Individuals were excluded if they were undergoing CBT; had an additional anxiety disorder, mood disorder, or current drug or alcohol use disorder, or any systemic disorder; had a history of seizures; were pregnant or breastfeeding; or had a history of memantine use.
• Participants already receiving the maximum tolerated dose of an SRI received augmentation with memantine 20 mg/d or placebo.
• The primary outcome measure was change in Y-BOCS score from baseline. The secondary outcome was the number of individuals who achieved treatment response (defined as ≥35% reduction in Y-BOCS score).

Continue to: Outcomes...

Outcomes

• There was a statistically significant difference in Y-BOCS score in patients treated with memantine at Week 8 and Week 12 vs those who received placebo. By Week 8, 17.2% of patients in the memantine group showed a decrease in Y-BOCS score, compared with -0.8% patients in the placebo group. The difference became more significant by Week 12, with 40.9% in the memantine group showing a decrease in Y-BOCS score vs -0.3% in the placebo group. This resulted in 73.3% of patients achieving treatment response.
• Eight weeks of memantine augmentation was necessary to observe a significant improvement in OCD symptoms, and 12 weeks was needed for treatment response.
• The mean Y-BOCS total score decreased significantly in the memantine group from Week 4 to Week 8 (16.8%) and again from Week 8 to Week 12 (28.5%).
• The memantine group showed good tolerability and safety. There were no clinically significant adverse effects.

Conclusion

• Memantine augmentation in patients with severe OCD who do not respond to an SRI is effective and well-tolerated.

4. Shalbafan M, Malekpour F, Tadayon Najafabadi B, et al. Fluvoxamine combination therapy with tropisetron for obsessive-compulsive disorder patients: a placebo-controlled, randomized clinical trial. J Psychopharmacol. 2019;33(11):1407- 1414. doi:10.1177/0269881119878177

Studies have demonstrated the involvement of the amygdala, medial and lateral orbitofrontal cortex, and dorsal anterior cingulate cortex in OCD. Additionally, studies have also investigated the role of serotonin, dopamine, and glutamate system dysregulation in the pathology of OCD.

The 5-HT3 receptors are ligand-gated ion channels found in the prefrontal cortex, amygdala, and hippocampus. Studies of 5-HT3 receptor antagonists such as ondansetron and granisetron have shown beneficial results in augmentation with SSRIs for patients with OCD.¹¹ Tropisetron, a 5-HT3 receptor antagonist, is highly lipophilic and able to cross the blood brain barrier. It also has dopamine-inhibiting properties that could have benefits in OCD management. Shalbafan et al¹³ evaluated the efficacy of tropisetron augmentation to fluvoxamine for patients with OCD.

Study design

• In a 10-week, randomized, double-blind, placebo-controlled, parallel-group trial, 108 individuals age 18 to 60 who met DSM-5 criteria for OCD and had a Y-BOCS score >21 received fluvoxamine plus tropisetron or fluvoxamine plus placebo. A total of 48 (44.4%) participants in each group completed the trial. Participants were evaluated using the Y-BOCS scale at baseline and at Week 4 and Week 10.
• The primary outcome was decrease in total Y-BOCS score from baseline to Week 10. The secondary outcome was the difference in change in Y-BOCS obsession and compulsion subscale scores between the groups.

Outcomes

• The Y-BOCS total score was not significantly different between the 2 groups (P = .975). Repeated measures analysis of variance determined a significant effect for time in both tropisetron and placebo groups (Greenhouse-Geisser F [2.72–2303.84] = 152.25, P < .001; and Greenhouse-Geisser F [1.37–1736.81] = 75.57, P < .001, respectively). At Week 10, 35 participants in the tropisetron group and 19 participants in the placebo group were complete responders.
• The baseline Y-BOCS obsession and compulsion subscales did not significantly differ between treatment groups.

Conclusion

• Compared with participants in the placebo group, those in the tropisetron group experienced a significantly greater reduction in OCD symptoms as measured by Y-BOCS score. More participants in the tropisetron group experienced complete response and remission.
• This study demonstrated that compared with placebo, when administered as augmentation with fluvoxamine, tropisetron can have beneficial effects for patients with OCD.

Continue to: Reference 5...

5. Yousefzadeh F, Sahebolzamani E, Sadri A, et al. 5-Hydroxytryptophan as adjuvant therapy in treatment of moderate to severe obsessive-compulsive disorder: a doubleblind randomized trial with placebo control. Int Clin Psychopharmacol. 2020;35(5):254- 262. doi:10.1097/YIC.0000000000000321

Nutraceuticals such as glycine, milk thistle, myoinositol, and serotonin (5-hydroxytryptophan) have been proposed as augmentation options for OCD. Yousefzadeh et al¹⁴ investigated the effectiveness of using 5-hydroxytryptophan in treating OCD.

Study design

• In a 12-week, randomized, double-blind study, 60 patients who met DSM-5 criteria for moderate to severe OCD (Y-BOCS score >21) were randomly assigned to receive fluoxetine plus 5-hydroxytryptophan 100 mg twice daily or fluoxetine plus placebo.
• All patients were administered fluoxetine 20 mg/d for the first 4 weeks of the study followed by fluoxetine 60 mg/d for the remainder of the trial.
• Symptoms were assessed using the Y-BOCS at baseline, Week 4, Week 8, and Week 12.
• The primary outcome measure was the difference between the 2 groups in change in Y-BOCS total score from baseline to the end of the trial. Secondary outcome measures were the differences in the Y-BOCS obsession and compulsion subscale scores from baseline to Week 12.

Outcomes

• Compared to the placebo group, the 5-hydroxytryptophan group experienced a statistically significant greater improvement in Y-BOCS total score from baseline to Week 8 (P = .002) and Week 12 (P < .001).
• General linear model repeated measure showed significant effects for time × treatment interaction on Y-BOCS total (F = 12.07, df = 2.29, P < .001), obsession subscale (F = 8.25, df = 1.91, P = .001), and compulsion subscale scores (F = 6.64, df = 2.01, P = .002).
• The 5-hydroxytryptophan group demonstrated higher partial and complete treatment response rates (P = .032 and P = .001, respectively) as determined by change in Y-BOCS total score.
• The 5-hydroxytryptophan group showed a significant improvement from baseline to Week 12 in Y-BOCS obsession subscale score (5.23 ± 2.33 vs 3.53 ± 2.13, P = .009).
• There was a significant change from baseline to the end of the trial in the Y-BOCS compulsion subscale score (3.88 ± 2.04 vs 2.30 ± 1.37, P = .002).

Conclusion

• This trial demonstrated the potential benefits of 5-hydroxytryptophan in combination with fluoxetine for patients with OCD.

6. Mowla A, Ghaedsharaf M. Pregabalin augmentation for resistant obsessive-compulsive disorder: a double-blind placebo-controlled clinical trial. CNS Spectr. 2020;25(4):552-556. doi:10.1017/S1092852919001500

Glutamatergic dysfunction has been identified as a potential cause of OCD. Studies have found elevated levels of glutamatergic transmission in the cortical-striatal-thalamic circuit of the brain and elevated glutamate concentration in the CSF in patients with OCD. Pregabalin has multiple mechanisms of action that inhibit the release of glutamate. Mowla et al¹⁵ evaluated pregabalin as an augmentation treatment for resistant OCD.

Study design

• This 12-week, double-blind, placebo-controlled clinical trial evaluated the efficacy of adjunctive pregabalin in 56 patients who met DSM-5 criteria for OCD and had not responded to ≥12 weeks of treatment with an adequate and stable dose of sertraline (baseline Y-BOCS score ≥18).
• Individuals who had other major psychiatric disorders, major medical problems, were pregnant, or had past substance or alcohol abuse were excluded.
• Participants were randomly assigned to receive sertraline plus pregabalin (n = 28) or sertraline plus placebo (n = 28). Mean sertraline dosage was 256.5 mg/d; range was 100 mg/d to 300 mg/d. Pregabalin was started at 75 mg/d and increased by 75 mg increments weekly. The mean dosage was 185.9 mg/d; range was 75 mg/d to 225 mg/d.
• The primary outcome measure was change in Y-BOCS score. A decrease >35% in Y-BOCS score was considered a significant response rate.

Outcomes

• There was a statistically significant decrease in Y-BOCS score in patients who received pregabalin. In the pregabalin group, 57.14% of patients (n = 16) showed a >35% decrease in Y-BOCS score compared with 7.14% of patients (n = 2) in the placebo group (P < .01).
• The pregabalin group showed good tolerability and safety. There were no clinically significant adverse effects.

Conclusion

• In patients with treatment-resistant OCD who did not respond to sertraline monotherapy, augmentation with pregabalin significantly decreases Y-BOCS scores compared with placebo.

Continue to: Reference 7...

Recent evidence suggests dysregulation of serotonin and dopamine in patients with OCD. Methylphenidate is a dopamine and norepinephrine inhibitor and releaser. A limited number of studies have suggested stimulants might be useful for OCD patients. Zheng et al¹⁶ conducted a pilot trial to determine whether methylphenidate augmentation may be of benefit in the management of outpatients with OCD.

Study design

• In an 8-week, double-blind, randomized, placebo-controlled trial, 44 patients (29 [66%] men, with a mean [SD] age of 24.7 [6]) with treatment-refractory OCD were randomized to receive fluvoxamine 250 mg/d plus methylphenidate extended-release (MPH-ER) 36 mg/d or fluvoxamine 250 mg/d plus placebo. The MPH-ER dose was 18 mg/d for the first 4 weeks and 36 mg/d for the rest of the trial.
• Biweekly assessments consisted of scores on the Y-BOCS, Hamilton Depression Rating Scale (HDRS), and Hamilton Anxiety Rating Scale (HAM-A).
• The primary outcomes were improvement in Y-BOCS score and the clinical response rate. Secondary outcomes included a change in score on the Y-BOCS subscales, HARS, and HAM-A. Data were analyzed with the intention-to-treat sample.

Outcomes

• Forty-one patients finished the trial. The baseline Y-BOCS total scores and subscale scores did not differ significantly between the 2 groups.
• Improvements in Y-BOCS total score and obsession subscale score were more prominent in the fluvoxamine plus MPH-ER group compared with the placebo group (P < .001).
• HDRS score decreased in both the placebo and MPH-ER groups. HAM-A scores decreased significantly in the MPH-ER plus fluvoxamine group compared with the placebo group.

Conclusion

• This study demonstrated that the combination of fluvoxamine and MPH-ER produces a higher and faster response rate than fluvoxamine plus placebo in patients with OCD.

8. Arabzadeh S, Shahhossenie M, Mesgarpour B, et al. L-carnosine as an adjuvant to fluvoxamine in treatment of obsessive compulsive disorder: a randomized double-blind study. Hum Psychopharmacol. 2017;32(4). doi:10.1002/hup.2584

Glutamate dysregulation is implicated in the pathogenesis of OCD. Glutamate-modulating agents have been used to treat OCD. Studies have shown L-carnosine has a neuroprotective role via its modulatory effect on glutamate. Arabzadeh et al¹⁷ evaluated the efficacy of L-carnosine as an adjuvant to fluvoxamine for treating OCD.

Study design

• This 10-week, randomized, double-blind, placebo-controlled trial evaluated the efficacy of adjunctive L-carnosine in 40 patients age 18 to 60 who met DSM-5 criteria for OCD and had moderate to severe OCD (Y-BOCS score ≥21).
• Individuals with any other DSM-5 major psychiatric disorders, serious medical or neurologic illness, substance dependence (other than caffeine or nicotine), mental retardation (based on clinical judgment), were pregnant or breastfeeding, had any contraindication for the use of L‐carnosine or fluvoxamine, or received any psychotropic drugs in the previous 6 weeks were excluded.
• Participants received fluvoxamine 100 mg/d for the first 4 weeks and 200 mg/d for the next 6 weeks plus either L-carnosine 500 mg twice daily or placebo. This dosage of L-carnosine was chosen because previously it had been tolerated and effective.
• The primary outcome measure was difference in Y-BOCS total scores. Secondary outcomes were differences in Y-BOCS obsession and compulsion subscale scores and differences in change in score on Y-BOCS total and subscale scores from baseline.

Outcomes

• The L-carnosine group experienced a significant decrease in Y-BOCS total score (P < .001), obsession subscale score (P < .01), and compulsion subscale score (P < .01).
• The group that received fluvoxamine plus L-carnosine also experienced a more complete response (P = .03).
• The L-carnosine group showed good tolerability and safety. There were no clinically significant adverse effects.

Conclusion

• L-carnosine significantly reduces OCD symptoms when used as an adjuvant to fluvoxamine.

Obsessive-compulsive disorder (OCD) is a chronic, debilitating neuropsychiatric disorder that affects 1% to 3% of the population worldwide.^1,2 Together, serotonin reuptake inhibitors (SRIs) and cognitive-behavior therapy (CBT) are considered the first-line treatment for OCD.³ In children and adults, CBT is considered at least as effective as pharmacotherapy.⁴ Despite being an effective treatment, CBT continues to have barriers to its widespread use, including limited availability of trained CBT therapists, delayed clinical response, and high costs.⁵

Only approximately one-half of patients with OCD respond to SRI therapy, and a considerable percentage (30% to 40%) show significant residual symptoms even after multiple trials of SRIs.^6-8 In addition, SRIs may have adverse effects (eg, sexual dysfunction, gastrointestinal symptoms) that impair patient adherence to these medications.⁹ Therefore, finding better treatment options is important for managing patients with OCD.

Augmentation strategies are recommended for patients who show partial response to SRI treatment or poor response to multiple SRIs. Augmentation typically includes incorporating additional medications with the primary drug with the goal of boosting the therapeutic efficacy of the primary drug. Typically, these additional medications have different mechanisms of action. However, there are no large-scale randomized controlled trials (RCTs) to inform treatment augmentation after first-line treatments for OCD produce suboptimal outcomes. The available evidence is predominantly based on small-scale RCTs, open-label trials, and case series.

In this article, we review the evidence for treatment augmentation strategies for OCD and summarize 8 studies that show promising results (Table^10-17). We focus only on pharmacologic agents and do not include other biological interventions, such as repetitive transcranial magnetic stimulation over supplementary motor area, ablative neurosurgery, or deep brain stimulation.

Continue to: Reference 1...

Numerous studies support the role of glutamate dysregulation in the pathophysiology of OCD. Cortico-striato-thalamo-cortical (CSTC) abnormalities play a major role in the pathophysiology of OCD as suggested by neuroimaging research studies that indicate glutamate is the fundamental neurotransmitter of the CSTC circuit. Dysregulation of glutamatergic signaling within this circuit has been linked to OCD. Patients with OCD have been found to have an increase of glutamate in the CSF. As a result, medications that affect glutamate levels can be used to treat patients with OCD who do not respond to first-line agents. In patients already taking SRIs, augmentation of glutamate-modulating medications can reduce OCD symptoms. As an uncompetitive antagonist of the N-methyl-d-aspartate (NMDA)-type glutamate receptor, amantadine has been proposed as 1 of these medications.

Naderi et al¹⁰ evaluated amantadine as augmentative therapy to fluvoxamine for treating patients with moderate to severe OCD.

Study design

• This 12-week, randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of amantadine as an augmentative agent to fluvoxamine in 106 patients age 18 to 60 with moderate to severe OCD.
• Participants met DSM-5 criteria for OCD and had a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score >21. Participants were excluded if they had any substance dependence; an IQ <70; any other Axis I mental disorder; any serious cardiac, renal, or hepatic disease; had received psychotropic medications during the last 6 weeks, were pregnant or breastfeeding, or had rising liver transaminases to 3 times the upper limit of normal or higher.
• Participants received fluvoxamine 100 mg twice daily plus amantadine 100 mg/d, or fluvoxamine 100 mg twice daily plus placebo. All patients received fluvoxamine 100 mg/d for 28 days followed by 200 mg/d for the remainder of the trial.
• The primary outcome measure was difference in Y-BOCS total scores between the amantadine and placebo groups. The secondary outcome was the difference in Y-BOCS obsession and compulsion subscale scores.

Outcomes

• Patients who received amantadine augmentation experienced a significant reduction in Y-BOCS total score (P < .001) and obsession subscale score (P < .01).
• The amantadine group showed good tolerability and safety. There were no clinically significant adverse effects.

• Amantadine is an effective adjuvant to fluvoxamine for reducing OCD symptoms.

Conclusion

• Ondansetron and granisetron can be beneficial as an augmentation strategy for patients with treatment-resistant OCD.

2. Sharafkhah M, Aghakarim Alamdar M, Massoudifar A, et al. Comparing the efficacy of ondansetron and granisetron augmentation in treatment-resistant obsessive-compulsive disorder: a randomized double-blind placebo-controlled study. Int Clin Psychopharmacol. 2019;34(5):222- 233. doi:10.1097/YIC.0000000000000267

Although selective serotonin reuptake inhibitors (SSRIs) are considered a first-line treatment when teamed with CBT and antipsychotic augmentation, symptom resolution is not always achieved, and treatment resistance is a common problem. Sharafkhah et al¹¹ compared the efficacy of ondansetron and granisetron augmentation specifically for patients with treatment-resistant OCD.

Study Design

• In this 18-week, randomized, double-blind, placebo-controlled study, 135 patients with treatment-resistant OCD who were previously treated with a combination of an SSRI and an antipsychotic received augmentation with ondansetron (n = 45, 4 mg/d), granisetron (n = 45, 2 mg/d), or placebo.
• Patients were rated using Y-BOCS every 2 weeks during phase I (intervention period), which lasted 14 weeks. After completing the intervention, patients were followed for 4 more weeks during phase II (discontinuation period).
• The aim of this study was to determine the safety, efficacy, and tolerability of ondansetron vs granisetron as augmentation for patients with treatment-resistant OCD. A secondary aim was to determine the rate of relapse of OCD symptoms after discontinuing ondansetron as compared with granisetron at 4 weeks after intervention.

Outcomes

• At Week 14, the reductions in Y-BOCS scores in the ondansetron, granisetron, and placebo groups were 41.5%, 39.7%, and 15.2%, respectively (P = .001). The reduction in Y-BOCS score in the ondansetron and granisetron groups was significantly greater than placebo at all phase I visits.
• Complete response was higher in the ondansetron group compared with the granisetron group (P = .041).
• Y-BOCS scores increased in both the ondansetron and granisetron groups during the discontinuation phase, but OCD symptoms were not significantly exacerbated.

Conclusion

• Ondansetron and granisetron can be beneficial as an augmentation strategy for patients with treatment-resistant OCD.

3. Modarresi A, Sayyah M, Razooghi S, et al. Memantine augmentation improves symptoms in serotonin reuptake inhibitorrefractory obsessive-compulsive disorder: a randomized controlled trial. Pharmacopsychiatry. 2018;51(6):263-269. doi:10.1055/s-0043-120268

Increased glutamate levels in CSF, glutamatergic overactivity, and polymorphisms of genes coding the NMDA receptor have been shown to contribute to the occurrence of OCD. Memantine is a noncompetitive antagonist of the NMDA receptor. Various control trials have shown augmentation with memantine 5 mg/d to 20 mg/d significantly reduced symptom severity in patients with moderate to severe OCD. Modarresi et al¹² evaluated memantine as a treatment option for patients with severe OCD who did not respond to SRI monotherapy.

Study design

• This 12-week, double-blind, randomized, placebo-controlled trial evaluated the efficacy of memantine augmentation in 32 patients age 18 to 40 who met DSM-5 criteria for OCD, had a Y-BOCS score ≥24, and no psychiatric comorbidity. Participants had not responded to ≥3 adequate trials (minimum 3 months) of SRI therapy, 1 of which was clomipramine.
• Individuals were excluded if they were undergoing CBT; had an additional anxiety disorder, mood disorder, or current drug or alcohol use disorder, or any systemic disorder; had a history of seizures; were pregnant or breastfeeding; or had a history of memantine use.
• Participants already receiving the maximum tolerated dose of an SRI received augmentation with memantine 20 mg/d or placebo.
• The primary outcome measure was change in Y-BOCS score from baseline. The secondary outcome was the number of individuals who achieved treatment response (defined as ≥35% reduction in Y-BOCS score).

Continue to: Outcomes...

Outcomes

• There was a statistically significant difference in Y-BOCS score in patients treated with memantine at Week 8 and Week 12 vs those who received placebo. By Week 8, 17.2% of patients in the memantine group showed a decrease in Y-BOCS score, compared with -0.8% patients in the placebo group. The difference became more significant by Week 12, with 40.9% in the memantine group showing a decrease in Y-BOCS score vs -0.3% in the placebo group. This resulted in 73.3% of patients achieving treatment response.
• Eight weeks of memantine augmentation was necessary to observe a significant improvement in OCD symptoms, and 12 weeks was needed for treatment response.
• The mean Y-BOCS total score decreased significantly in the memantine group from Week 4 to Week 8 (16.8%) and again from Week 8 to Week 12 (28.5%).
• The memantine group showed good tolerability and safety. There were no clinically significant adverse effects.

Conclusion

• Memantine augmentation in patients with severe OCD who do not respond to an SRI is effective and well-tolerated.

4. Shalbafan M, Malekpour F, Tadayon Najafabadi B, et al. Fluvoxamine combination therapy with tropisetron for obsessive-compulsive disorder patients: a placebo-controlled, randomized clinical trial. J Psychopharmacol. 2019;33(11):1407- 1414. doi:10.1177/0269881119878177

Studies have demonstrated the involvement of the amygdala, medial and lateral orbitofrontal cortex, and dorsal anterior cingulate cortex in OCD. Additionally, studies have also investigated the role of serotonin, dopamine, and glutamate system dysregulation in the pathology of OCD.

The 5-HT3 receptors are ligand-gated ion channels found in the prefrontal cortex, amygdala, and hippocampus. Studies of 5-HT3 receptor antagonists such as ondansetron and granisetron have shown beneficial results in augmentation with SSRIs for patients with OCD.¹¹ Tropisetron, a 5-HT3 receptor antagonist, is highly lipophilic and able to cross the blood brain barrier. It also has dopamine-inhibiting properties that could have benefits in OCD management. Shalbafan et al¹³ evaluated the efficacy of tropisetron augmentation to fluvoxamine for patients with OCD.

Study design

• In a 10-week, randomized, double-blind, placebo-controlled, parallel-group trial, 108 individuals age 18 to 60 who met DSM-5 criteria for OCD and had a Y-BOCS score >21 received fluvoxamine plus tropisetron or fluvoxamine plus placebo. A total of 48 (44.4%) participants in each group completed the trial. Participants were evaluated using the Y-BOCS scale at baseline and at Week 4 and Week 10.
• The primary outcome was decrease in total Y-BOCS score from baseline to Week 10. The secondary outcome was the difference in change in Y-BOCS obsession and compulsion subscale scores between the groups.

Outcomes

• The Y-BOCS total score was not significantly different between the 2 groups (P = .975). Repeated measures analysis of variance determined a significant effect for time in both tropisetron and placebo groups (Greenhouse-Geisser F [2.72–2303.84] = 152.25, P < .001; and Greenhouse-Geisser F [1.37–1736.81] = 75.57, P < .001, respectively). At Week 10, 35 participants in the tropisetron group and 19 participants in the placebo group were complete responders.
• The baseline Y-BOCS obsession and compulsion subscales did not significantly differ between treatment groups.

Conclusion

• Compared with participants in the placebo group, those in the tropisetron group experienced a significantly greater reduction in OCD symptoms as measured by Y-BOCS score. More participants in the tropisetron group experienced complete response and remission.
• This study demonstrated that compared with placebo, when administered as augmentation with fluvoxamine, tropisetron can have beneficial effects for patients with OCD.

Continue to: Reference 5...

5. Yousefzadeh F, Sahebolzamani E, Sadri A, et al. 5-Hydroxytryptophan as adjuvant therapy in treatment of moderate to severe obsessive-compulsive disorder: a doubleblind randomized trial with placebo control. Int Clin Psychopharmacol. 2020;35(5):254- 262. doi:10.1097/YIC.0000000000000321

Nutraceuticals such as glycine, milk thistle, myoinositol, and serotonin (5-hydroxytryptophan) have been proposed as augmentation options for OCD. Yousefzadeh et al¹⁴ investigated the effectiveness of using 5-hydroxytryptophan in treating OCD.

Study design

• In a 12-week, randomized, double-blind study, 60 patients who met DSM-5 criteria for moderate to severe OCD (Y-BOCS score >21) were randomly assigned to receive fluoxetine plus 5-hydroxytryptophan 100 mg twice daily or fluoxetine plus placebo.
• All patients were administered fluoxetine 20 mg/d for the first 4 weeks of the study followed by fluoxetine 60 mg/d for the remainder of the trial.
• Symptoms were assessed using the Y-BOCS at baseline, Week 4, Week 8, and Week 12.
• The primary outcome measure was the difference between the 2 groups in change in Y-BOCS total score from baseline to the end of the trial. Secondary outcome measures were the differences in the Y-BOCS obsession and compulsion subscale scores from baseline to Week 12.

Outcomes

• Compared to the placebo group, the 5-hydroxytryptophan group experienced a statistically significant greater improvement in Y-BOCS total score from baseline to Week 8 (P = .002) and Week 12 (P < .001).
• General linear model repeated measure showed significant effects for time × treatment interaction on Y-BOCS total (F = 12.07, df = 2.29, P < .001), obsession subscale (F = 8.25, df = 1.91, P = .001), and compulsion subscale scores (F = 6.64, df = 2.01, P = .002).
• The 5-hydroxytryptophan group demonstrated higher partial and complete treatment response rates (P = .032 and P = .001, respectively) as determined by change in Y-BOCS total score.
• The 5-hydroxytryptophan group showed a significant improvement from baseline to Week 12 in Y-BOCS obsession subscale score (5.23 ± 2.33 vs 3.53 ± 2.13, P = .009).
• There was a significant change from baseline to the end of the trial in the Y-BOCS compulsion subscale score (3.88 ± 2.04 vs 2.30 ± 1.37, P = .002).

Conclusion

• This trial demonstrated the potential benefits of 5-hydroxytryptophan in combination with fluoxetine for patients with OCD.

6. Mowla A, Ghaedsharaf M. Pregabalin augmentation for resistant obsessive-compulsive disorder: a double-blind placebo-controlled clinical trial. CNS Spectr. 2020;25(4):552-556. doi:10.1017/S1092852919001500

Glutamatergic dysfunction has been identified as a potential cause of OCD. Studies have found elevated levels of glutamatergic transmission in the cortical-striatal-thalamic circuit of the brain and elevated glutamate concentration in the CSF in patients with OCD. Pregabalin has multiple mechanisms of action that inhibit the release of glutamate. Mowla et al¹⁵ evaluated pregabalin as an augmentation treatment for resistant OCD.

Study design

• This 12-week, double-blind, placebo-controlled clinical trial evaluated the efficacy of adjunctive pregabalin in 56 patients who met DSM-5 criteria for OCD and had not responded to ≥12 weeks of treatment with an adequate and stable dose of sertraline (baseline Y-BOCS score ≥18).
• Individuals who had other major psychiatric disorders, major medical problems, were pregnant, or had past substance or alcohol abuse were excluded.
• Participants were randomly assigned to receive sertraline plus pregabalin (n = 28) or sertraline plus placebo (n = 28). Mean sertraline dosage was 256.5 mg/d; range was 100 mg/d to 300 mg/d. Pregabalin was started at 75 mg/d and increased by 75 mg increments weekly. The mean dosage was 185.9 mg/d; range was 75 mg/d to 225 mg/d.
• The primary outcome measure was change in Y-BOCS score. A decrease >35% in Y-BOCS score was considered a significant response rate.

Outcomes

• There was a statistically significant decrease in Y-BOCS score in patients who received pregabalin. In the pregabalin group, 57.14% of patients (n = 16) showed a >35% decrease in Y-BOCS score compared with 7.14% of patients (n = 2) in the placebo group (P < .01).
• The pregabalin group showed good tolerability and safety. There were no clinically significant adverse effects.

Conclusion

• In patients with treatment-resistant OCD who did not respond to sertraline monotherapy, augmentation with pregabalin significantly decreases Y-BOCS scores compared with placebo.

Continue to: Reference 7...

Recent evidence suggests dysregulation of serotonin and dopamine in patients with OCD. Methylphenidate is a dopamine and norepinephrine inhibitor and releaser. A limited number of studies have suggested stimulants might be useful for OCD patients. Zheng et al¹⁶ conducted a pilot trial to determine whether methylphenidate augmentation may be of benefit in the management of outpatients with OCD.

Study design

• In an 8-week, double-blind, randomized, placebo-controlled trial, 44 patients (29 [66%] men, with a mean [SD] age of 24.7 [6]) with treatment-refractory OCD were randomized to receive fluvoxamine 250 mg/d plus methylphenidate extended-release (MPH-ER) 36 mg/d or fluvoxamine 250 mg/d plus placebo. The MPH-ER dose was 18 mg/d for the first 4 weeks and 36 mg/d for the rest of the trial.
• Biweekly assessments consisted of scores on the Y-BOCS, Hamilton Depression Rating Scale (HDRS), and Hamilton Anxiety Rating Scale (HAM-A).
• The primary outcomes were improvement in Y-BOCS score and the clinical response rate. Secondary outcomes included a change in score on the Y-BOCS subscales, HARS, and HAM-A. Data were analyzed with the intention-to-treat sample.

Outcomes

• Forty-one patients finished the trial. The baseline Y-BOCS total scores and subscale scores did not differ significantly between the 2 groups.
• Improvements in Y-BOCS total score and obsession subscale score were more prominent in the fluvoxamine plus MPH-ER group compared with the placebo group (P < .001).
• HDRS score decreased in both the placebo and MPH-ER groups. HAM-A scores decreased significantly in the MPH-ER plus fluvoxamine group compared with the placebo group.

Conclusion

• This study demonstrated that the combination of fluvoxamine and MPH-ER produces a higher and faster response rate than fluvoxamine plus placebo in patients with OCD.

8. Arabzadeh S, Shahhossenie M, Mesgarpour B, et al. L-carnosine as an adjuvant to fluvoxamine in treatment of obsessive compulsive disorder: a randomized double-blind study. Hum Psychopharmacol. 2017;32(4). doi:10.1002/hup.2584

Glutamate dysregulation is implicated in the pathogenesis of OCD. Glutamate-modulating agents have been used to treat OCD. Studies have shown L-carnosine has a neuroprotective role via its modulatory effect on glutamate. Arabzadeh et al¹⁷ evaluated the efficacy of L-carnosine as an adjuvant to fluvoxamine for treating OCD.

Study design

• This 10-week, randomized, double-blind, placebo-controlled trial evaluated the efficacy of adjunctive L-carnosine in 40 patients age 18 to 60 who met DSM-5 criteria for OCD and had moderate to severe OCD (Y-BOCS score ≥21).
• Individuals with any other DSM-5 major psychiatric disorders, serious medical or neurologic illness, substance dependence (other than caffeine or nicotine), mental retardation (based on clinical judgment), were pregnant or breastfeeding, had any contraindication for the use of L‐carnosine or fluvoxamine, or received any psychotropic drugs in the previous 6 weeks were excluded.
• Participants received fluvoxamine 100 mg/d for the first 4 weeks and 200 mg/d for the next 6 weeks plus either L-carnosine 500 mg twice daily or placebo. This dosage of L-carnosine was chosen because previously it had been tolerated and effective.
• The primary outcome measure was difference in Y-BOCS total scores. Secondary outcomes were differences in Y-BOCS obsession and compulsion subscale scores and differences in change in score on Y-BOCS total and subscale scores from baseline.

Outcomes

• The L-carnosine group experienced a significant decrease in Y-BOCS total score (P < .001), obsession subscale score (P < .01), and compulsion subscale score (P < .01).
• The group that received fluvoxamine plus L-carnosine also experienced a more complete response (P = .03).
• The L-carnosine group showed good tolerability and safety. There were no clinically significant adverse effects.

Conclusion

• L-carnosine significantly reduces OCD symptoms when used as an adjuvant to fluvoxamine.

Obsessive-compulsive disorder (OCD) is a chronic, debilitating neuropsychiatric disorder that affects 1% to 3% of the population worldwide.^1,2 Together, serotonin reuptake inhibitors (SRIs) and cognitive-behavior therapy (CBT) are considered the first-line treatment for OCD.³ In children and adults, CBT is considered at least as effective as pharmacotherapy.⁴ Despite being an effective treatment, CBT continues to have barriers to its widespread use, including limited availability of trained CBT therapists, delayed clinical response, and high costs.⁵

Only approximately one-half of patients with OCD respond to SRI therapy, and a considerable percentage (30% to 40%) show significant residual symptoms even after multiple trials of SRIs.^6-8 In addition, SRIs may have adverse effects (eg, sexual dysfunction, gastrointestinal symptoms) that impair patient adherence to these medications.⁹ Therefore, finding better treatment options is important for managing patients with OCD.

Augmentation strategies are recommended for patients who show partial response to SRI treatment or poor response to multiple SRIs. Augmentation typically includes incorporating additional medications with the primary drug with the goal of boosting the therapeutic efficacy of the primary drug. Typically, these additional medications have different mechanisms of action. However, there are no large-scale randomized controlled trials (RCTs) to inform treatment augmentation after first-line treatments for OCD produce suboptimal outcomes. The available evidence is predominantly based on small-scale RCTs, open-label trials, and case series.

In this article, we review the evidence for treatment augmentation strategies for OCD and summarize 8 studies that show promising results (Table^10-17). We focus only on pharmacologic agents and do not include other biological interventions, such as repetitive transcranial magnetic stimulation over supplementary motor area, ablative neurosurgery, or deep brain stimulation.

Continue to: Reference 1...

Numerous studies support the role of glutamate dysregulation in the pathophysiology of OCD. Cortico-striato-thalamo-cortical (CSTC) abnormalities play a major role in the pathophysiology of OCD as suggested by neuroimaging research studies that indicate glutamate is the fundamental neurotransmitter of the CSTC circuit. Dysregulation of glutamatergic signaling within this circuit has been linked to OCD. Patients with OCD have been found to have an increase of glutamate in the CSF. As a result, medications that affect glutamate levels can be used to treat patients with OCD who do not respond to first-line agents. In patients already taking SRIs, augmentation of glutamate-modulating medications can reduce OCD symptoms. As an uncompetitive antagonist of the N-methyl-d-aspartate (NMDA)-type glutamate receptor, amantadine has been proposed as 1 of these medications.

Naderi et al¹⁰ evaluated amantadine as augmentative therapy to fluvoxamine for treating patients with moderate to severe OCD.

Study design

• This 12-week, randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of amantadine as an augmentative agent to fluvoxamine in 106 patients age 18 to 60 with moderate to severe OCD.
• Participants met DSM-5 criteria for OCD and had a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score >21. Participants were excluded if they had any substance dependence; an IQ <70; any other Axis I mental disorder; any serious cardiac, renal, or hepatic disease; had received psychotropic medications during the last 6 weeks, were pregnant or breastfeeding, or had rising liver transaminases to 3 times the upper limit of normal or higher.
• Participants received fluvoxamine 100 mg twice daily plus amantadine 100 mg/d, or fluvoxamine 100 mg twice daily plus placebo. All patients received fluvoxamine 100 mg/d for 28 days followed by 200 mg/d for the remainder of the trial.
• The primary outcome measure was difference in Y-BOCS total scores between the amantadine and placebo groups. The secondary outcome was the difference in Y-BOCS obsession and compulsion subscale scores.

Outcomes

• Patients who received amantadine augmentation experienced a significant reduction in Y-BOCS total score (P < .001) and obsession subscale score (P < .01).
• The amantadine group showed good tolerability and safety. There were no clinically significant adverse effects.

• Amantadine is an effective adjuvant to fluvoxamine for reducing OCD symptoms.

Conclusion

• Ondansetron and granisetron can be beneficial as an augmentation strategy for patients with treatment-resistant OCD.

2. Sharafkhah M, Aghakarim Alamdar M, Massoudifar A, et al. Comparing the efficacy of ondansetron and granisetron augmentation in treatment-resistant obsessive-compulsive disorder: a randomized double-blind placebo-controlled study. Int Clin Psychopharmacol. 2019;34(5):222- 233. doi:10.1097/YIC.0000000000000267

Although selective serotonin reuptake inhibitors (SSRIs) are considered a first-line treatment when teamed with CBT and antipsychotic augmentation, symptom resolution is not always achieved, and treatment resistance is a common problem. Sharafkhah et al¹¹ compared the efficacy of ondansetron and granisetron augmentation specifically for patients with treatment-resistant OCD.

Study Design

• In this 18-week, randomized, double-blind, placebo-controlled study, 135 patients with treatment-resistant OCD who were previously treated with a combination of an SSRI and an antipsychotic received augmentation with ondansetron (n = 45, 4 mg/d), granisetron (n = 45, 2 mg/d), or placebo.
• Patients were rated using Y-BOCS every 2 weeks during phase I (intervention period), which lasted 14 weeks. After completing the intervention, patients were followed for 4 more weeks during phase II (discontinuation period).
• The aim of this study was to determine the safety, efficacy, and tolerability of ondansetron vs granisetron as augmentation for patients with treatment-resistant OCD. A secondary aim was to determine the rate of relapse of OCD symptoms after discontinuing ondansetron as compared with granisetron at 4 weeks after intervention.

Outcomes

• At Week 14, the reductions in Y-BOCS scores in the ondansetron, granisetron, and placebo groups were 41.5%, 39.7%, and 15.2%, respectively (P = .001). The reduction in Y-BOCS score in the ondansetron and granisetron groups was significantly greater than placebo at all phase I visits.
• Complete response was higher in the ondansetron group compared with the granisetron group (P = .041).
• Y-BOCS scores increased in both the ondansetron and granisetron groups during the discontinuation phase, but OCD symptoms were not significantly exacerbated.

Conclusion

• Ondansetron and granisetron can be beneficial as an augmentation strategy for patients with treatment-resistant OCD.

3. Modarresi A, Sayyah M, Razooghi S, et al. Memantine augmentation improves symptoms in serotonin reuptake inhibitorrefractory obsessive-compulsive disorder: a randomized controlled trial. Pharmacopsychiatry. 2018;51(6):263-269. doi:10.1055/s-0043-120268

Increased glutamate levels in CSF, glutamatergic overactivity, and polymorphisms of genes coding the NMDA receptor have been shown to contribute to the occurrence of OCD. Memantine is a noncompetitive antagonist of the NMDA receptor. Various control trials have shown augmentation with memantine 5 mg/d to 20 mg/d significantly reduced symptom severity in patients with moderate to severe OCD. Modarresi et al¹² evaluated memantine as a treatment option for patients with severe OCD who did not respond to SRI monotherapy.

Study design

• This 12-week, double-blind, randomized, placebo-controlled trial evaluated the efficacy of memantine augmentation in 32 patients age 18 to 40 who met DSM-5 criteria for OCD, had a Y-BOCS score ≥24, and no psychiatric comorbidity. Participants had not responded to ≥3 adequate trials (minimum 3 months) of SRI therapy, 1 of which was clomipramine.
• Individuals were excluded if they were undergoing CBT; had an additional anxiety disorder, mood disorder, or current drug or alcohol use disorder, or any systemic disorder; had a history of seizures; were pregnant or breastfeeding; or had a history of memantine use.
• Participants already receiving the maximum tolerated dose of an SRI received augmentation with memantine 20 mg/d or placebo.
• The primary outcome measure was change in Y-BOCS score from baseline. The secondary outcome was the number of individuals who achieved treatment response (defined as ≥35% reduction in Y-BOCS score).

Continue to: Outcomes...

Outcomes

• There was a statistically significant difference in Y-BOCS score in patients treated with memantine at Week 8 and Week 12 vs those who received placebo. By Week 8, 17.2% of patients in the memantine group showed a decrease in Y-BOCS score, compared with -0.8% patients in the placebo group. The difference became more significant by Week 12, with 40.9% in the memantine group showing a decrease in Y-BOCS score vs -0.3% in the placebo group. This resulted in 73.3% of patients achieving treatment response.
• Eight weeks of memantine augmentation was necessary to observe a significant improvement in OCD symptoms, and 12 weeks was needed for treatment response.
• The mean Y-BOCS total score decreased significantly in the memantine group from Week 4 to Week 8 (16.8%) and again from Week 8 to Week 12 (28.5%).
• The memantine group showed good tolerability and safety. There were no clinically significant adverse effects.

Conclusion

• Memantine augmentation in patients with severe OCD who do not respond to an SRI is effective and well-tolerated.

4. Shalbafan M, Malekpour F, Tadayon Najafabadi B, et al. Fluvoxamine combination therapy with tropisetron for obsessive-compulsive disorder patients: a placebo-controlled, randomized clinical trial. J Psychopharmacol. 2019;33(11):1407- 1414. doi:10.1177/0269881119878177

Studies have demonstrated the involvement of the amygdala, medial and lateral orbitofrontal cortex, and dorsal anterior cingulate cortex in OCD. Additionally, studies have also investigated the role of serotonin, dopamine, and glutamate system dysregulation in the pathology of OCD.

The 5-HT3 receptors are ligand-gated ion channels found in the prefrontal cortex, amygdala, and hippocampus. Studies of 5-HT3 receptor antagonists such as ondansetron and granisetron have shown beneficial results in augmentation with SSRIs for patients with OCD.¹¹ Tropisetron, a 5-HT3 receptor antagonist, is highly lipophilic and able to cross the blood brain barrier. It also has dopamine-inhibiting properties that could have benefits in OCD management. Shalbafan et al¹³ evaluated the efficacy of tropisetron augmentation to fluvoxamine for patients with OCD.

Study design

• In a 10-week, randomized, double-blind, placebo-controlled, parallel-group trial, 108 individuals age 18 to 60 who met DSM-5 criteria for OCD and had a Y-BOCS score >21 received fluvoxamine plus tropisetron or fluvoxamine plus placebo. A total of 48 (44.4%) participants in each group completed the trial. Participants were evaluated using the Y-BOCS scale at baseline and at Week 4 and Week 10.
• The primary outcome was decrease in total Y-BOCS score from baseline to Week 10. The secondary outcome was the difference in change in Y-BOCS obsession and compulsion subscale scores between the groups.

Outcomes

• The Y-BOCS total score was not significantly different between the 2 groups (P = .975). Repeated measures analysis of variance determined a significant effect for time in both tropisetron and placebo groups (Greenhouse-Geisser F [2.72–2303.84] = 152.25, P < .001; and Greenhouse-Geisser F [1.37–1736.81] = 75.57, P < .001, respectively). At Week 10, 35 participants in the tropisetron group and 19 participants in the placebo group were complete responders.
• The baseline Y-BOCS obsession and compulsion subscales did not significantly differ between treatment groups.

Conclusion

• Compared with participants in the placebo group, those in the tropisetron group experienced a significantly greater reduction in OCD symptoms as measured by Y-BOCS score. More participants in the tropisetron group experienced complete response and remission.
• This study demonstrated that compared with placebo, when administered as augmentation with fluvoxamine, tropisetron can have beneficial effects for patients with OCD.

Continue to: Reference 5...

5. Yousefzadeh F, Sahebolzamani E, Sadri A, et al. 5-Hydroxytryptophan as adjuvant therapy in treatment of moderate to severe obsessive-compulsive disorder: a doubleblind randomized trial with placebo control. Int Clin Psychopharmacol. 2020;35(5):254- 262. doi:10.1097/YIC.0000000000000321

Nutraceuticals such as glycine, milk thistle, myoinositol, and serotonin (5-hydroxytryptophan) have been proposed as augmentation options for OCD. Yousefzadeh et al¹⁴ investigated the effectiveness of using 5-hydroxytryptophan in treating OCD.

Study design

• In a 12-week, randomized, double-blind study, 60 patients who met DSM-5 criteria for moderate to severe OCD (Y-BOCS score >21) were randomly assigned to receive fluoxetine plus 5-hydroxytryptophan 100 mg twice daily or fluoxetine plus placebo.
• All patients were administered fluoxetine 20 mg/d for the first 4 weeks of the study followed by fluoxetine 60 mg/d for the remainder of the trial.
• Symptoms were assessed using the Y-BOCS at baseline, Week 4, Week 8, and Week 12.
• The primary outcome measure was the difference between the 2 groups in change in Y-BOCS total score from baseline to the end of the trial. Secondary outcome measures were the differences in the Y-BOCS obsession and compulsion subscale scores from baseline to Week 12.

Outcomes

• Compared to the placebo group, the 5-hydroxytryptophan group experienced a statistically significant greater improvement in Y-BOCS total score from baseline to Week 8 (P = .002) and Week 12 (P < .001).
• General linear model repeated measure showed significant effects for time × treatment interaction on Y-BOCS total (F = 12.07, df = 2.29, P < .001), obsession subscale (F = 8.25, df = 1.91, P = .001), and compulsion subscale scores (F = 6.64, df = 2.01, P = .002).
• The 5-hydroxytryptophan group demonstrated higher partial and complete treatment response rates (P = .032 and P = .001, respectively) as determined by change in Y-BOCS total score.
• The 5-hydroxytryptophan group showed a significant improvement from baseline to Week 12 in Y-BOCS obsession subscale score (5.23 ± 2.33 vs 3.53 ± 2.13, P = .009).
• There was a significant change from baseline to the end of the trial in the Y-BOCS compulsion subscale score (3.88 ± 2.04 vs 2.30 ± 1.37, P = .002).

Conclusion

• This trial demonstrated the potential benefits of 5-hydroxytryptophan in combination with fluoxetine for patients with OCD.

6. Mowla A, Ghaedsharaf M. Pregabalin augmentation for resistant obsessive-compulsive disorder: a double-blind placebo-controlled clinical trial. CNS Spectr. 2020;25(4):552-556. doi:10.1017/S1092852919001500

Glutamatergic dysfunction has been identified as a potential cause of OCD. Studies have found elevated levels of glutamatergic transmission in the cortical-striatal-thalamic circuit of the brain and elevated glutamate concentration in the CSF in patients with OCD. Pregabalin has multiple mechanisms of action that inhibit the release of glutamate. Mowla et al¹⁵ evaluated pregabalin as an augmentation treatment for resistant OCD.

Study design

• This 12-week, double-blind, placebo-controlled clinical trial evaluated the efficacy of adjunctive pregabalin in 56 patients who met DSM-5 criteria for OCD and had not responded to ≥12 weeks of treatment with an adequate and stable dose of sertraline (baseline Y-BOCS score ≥18).
• Individuals who had other major psychiatric disorders, major medical problems, were pregnant, or had past substance or alcohol abuse were excluded.
• Participants were randomly assigned to receive sertraline plus pregabalin (n = 28) or sertraline plus placebo (n = 28). Mean sertraline dosage was 256.5 mg/d; range was 100 mg/d to 300 mg/d. Pregabalin was started at 75 mg/d and increased by 75 mg increments weekly. The mean dosage was 185.9 mg/d; range was 75 mg/d to 225 mg/d.
• The primary outcome measure was change in Y-BOCS score. A decrease >35% in Y-BOCS score was considered a significant response rate.

Outcomes

• There was a statistically significant decrease in Y-BOCS score in patients who received pregabalin. In the pregabalin group, 57.14% of patients (n = 16) showed a >35% decrease in Y-BOCS score compared with 7.14% of patients (n = 2) in the placebo group (P < .01).
• The pregabalin group showed good tolerability and safety. There were no clinically significant adverse effects.

Conclusion

• In patients with treatment-resistant OCD who did not respond to sertraline monotherapy, augmentation with pregabalin significantly decreases Y-BOCS scores compared with placebo.

Continue to: Reference 7...

Recent evidence suggests dysregulation of serotonin and dopamine in patients with OCD. Methylphenidate is a dopamine and norepinephrine inhibitor and releaser. A limited number of studies have suggested stimulants might be useful for OCD patients. Zheng et al¹⁶ conducted a pilot trial to determine whether methylphenidate augmentation may be of benefit in the management of outpatients with OCD.

Study design

• In an 8-week, double-blind, randomized, placebo-controlled trial, 44 patients (29 [66%] men, with a mean [SD] age of 24.7 [6]) with treatment-refractory OCD were randomized to receive fluvoxamine 250 mg/d plus methylphenidate extended-release (MPH-ER) 36 mg/d or fluvoxamine 250 mg/d plus placebo. The MPH-ER dose was 18 mg/d for the first 4 weeks and 36 mg/d for the rest of the trial.
• Biweekly assessments consisted of scores on the Y-BOCS, Hamilton Depression Rating Scale (HDRS), and Hamilton Anxiety Rating Scale (HAM-A).
• The primary outcomes were improvement in Y-BOCS score and the clinical response rate. Secondary outcomes included a change in score on the Y-BOCS subscales, HARS, and HAM-A. Data were analyzed with the intention-to-treat sample.

Outcomes

• Forty-one patients finished the trial. The baseline Y-BOCS total scores and subscale scores did not differ significantly between the 2 groups.
• Improvements in Y-BOCS total score and obsession subscale score were more prominent in the fluvoxamine plus MPH-ER group compared with the placebo group (P < .001).
• HDRS score decreased in both the placebo and MPH-ER groups. HAM-A scores decreased significantly in the MPH-ER plus fluvoxamine group compared with the placebo group.

Conclusion

• This study demonstrated that the combination of fluvoxamine and MPH-ER produces a higher and faster response rate than fluvoxamine plus placebo in patients with OCD.

8. Arabzadeh S, Shahhossenie M, Mesgarpour B, et al. L-carnosine as an adjuvant to fluvoxamine in treatment of obsessive compulsive disorder: a randomized double-blind study. Hum Psychopharmacol. 2017;32(4). doi:10.1002/hup.2584

Glutamate dysregulation is implicated in the pathogenesis of OCD. Glutamate-modulating agents have been used to treat OCD. Studies have shown L-carnosine has a neuroprotective role via its modulatory effect on glutamate. Arabzadeh et al¹⁷ evaluated the efficacy of L-carnosine as an adjuvant to fluvoxamine for treating OCD.

Study design

• This 10-week, randomized, double-blind, placebo-controlled trial evaluated the efficacy of adjunctive L-carnosine in 40 patients age 18 to 60 who met DSM-5 criteria for OCD and had moderate to severe OCD (Y-BOCS score ≥21).
• Individuals with any other DSM-5 major psychiatric disorders, serious medical or neurologic illness, substance dependence (other than caffeine or nicotine), mental retardation (based on clinical judgment), were pregnant or breastfeeding, had any contraindication for the use of L‐carnosine or fluvoxamine, or received any psychotropic drugs in the previous 6 weeks were excluded.
• Participants received fluvoxamine 100 mg/d for the first 4 weeks and 200 mg/d for the next 6 weeks plus either L-carnosine 500 mg twice daily or placebo. This dosage of L-carnosine was chosen because previously it had been tolerated and effective.
• The primary outcome measure was difference in Y-BOCS total scores. Secondary outcomes were differences in Y-BOCS obsession and compulsion subscale scores and differences in change in score on Y-BOCS total and subscale scores from baseline.

Outcomes

• The L-carnosine group experienced a significant decrease in Y-BOCS total score (P < .001), obsession subscale score (P < .01), and compulsion subscale score (P < .01).
• The group that received fluvoxamine plus L-carnosine also experienced a more complete response (P = .03).
• The L-carnosine group showed good tolerability and safety. There were no clinically significant adverse effects.

Conclusion

• L-carnosine significantly reduces OCD symptoms when used as an adjuvant to fluvoxamine.