The Federal Trade Commission’s announcement June 7 of a plan to investigate the business practices of pharmacy benefit managers (PBMs) was welcome news to rheumatologists. Widespread concern about the cost of prescription drugs and an additional 24,000 comments from the public prompted the agency’s decision to examine PBMs, which act as intermediaries between insurers, manufacturers, and pharmacies.

PBMs negotiate drug prices and rebates with manufacturers, reimburse pharmacies for drug costs, and create insurers’ drug formularies. But it’s widely held that instead of managing and leveling costs, PBMs have ratcheted up prices at multiple junctures to gain more profit.

The FTC’s investigation will focus on the six largest PBMs: CVS Caremark, Express Scripts, OptumRx, Humana, Prime Therapeutics, and MedImpact Healthcare Systems. CVS Caremark is owned by CVS, Express Scripts is owned by Cigna, and OptumRx is owned by UnitedHealth. The companies will have 90 days to respond to the commission’s official request for information.

Some of the information the FTC plans to ask about includes how the companies may be pushing patients toward using PBM-owned pharmacies and how rebates affect insurers’ formularies and the cost of drugs for patients.

The purchase or establishment of PBMs by the largest insurance companies – known as vertical integration – makes it nearly impossible for outsiders to determine what’s really causing price increases for prescription drugs. “The black box of secretive contracts and monies changing hands between manufacturers and PBMs has grown quite large since the Department of Justice and the FTC allowed the big three PBMs to be part of the three largest health insurance companies,” Madelaine A. Feldman, MD, a rheumatologist at the Rheumatology Group, New Orleans, and president of the Coalition of State Rheumatology Organizations, told this news organization.

A version of this article first appeared on Medscape.com.

The Federal Trade Commission’s announcement June 7 of a plan to investigate the business practices of pharmacy benefit managers (PBMs) was welcome news to rheumatologists. Widespread concern about the cost of prescription drugs and an additional 24,000 comments from the public prompted the agency’s decision to examine PBMs, which act as intermediaries between insurers, manufacturers, and pharmacies.

PBMs negotiate drug prices and rebates with manufacturers, reimburse pharmacies for drug costs, and create insurers’ drug formularies. But it’s widely held that instead of managing and leveling costs, PBMs have ratcheted up prices at multiple junctures to gain more profit.

The FTC’s investigation will focus on the six largest PBMs: CVS Caremark, Express Scripts, OptumRx, Humana, Prime Therapeutics, and MedImpact Healthcare Systems. CVS Caremark is owned by CVS, Express Scripts is owned by Cigna, and OptumRx is owned by UnitedHealth. The companies will have 90 days to respond to the commission’s official request for information.

Some of the information the FTC plans to ask about includes how the companies may be pushing patients toward using PBM-owned pharmacies and how rebates affect insurers’ formularies and the cost of drugs for patients.

The purchase or establishment of PBMs by the largest insurance companies – known as vertical integration – makes it nearly impossible for outsiders to determine what’s really causing price increases for prescription drugs. “The black box of secretive contracts and monies changing hands between manufacturers and PBMs has grown quite large since the Department of Justice and the FTC allowed the big three PBMs to be part of the three largest health insurance companies,” Madelaine A. Feldman, MD, a rheumatologist at the Rheumatology Group, New Orleans, and president of the Coalition of State Rheumatology Organizations, told this news organization.

A version of this article first appeared on Medscape.com.

The Federal Trade Commission’s announcement June 7 of a plan to investigate the business practices of pharmacy benefit managers (PBMs) was welcome news to rheumatologists. Widespread concern about the cost of prescription drugs and an additional 24,000 comments from the public prompted the agency’s decision to examine PBMs, which act as intermediaries between insurers, manufacturers, and pharmacies.

PBMs negotiate drug prices and rebates with manufacturers, reimburse pharmacies for drug costs, and create insurers’ drug formularies. But it’s widely held that instead of managing and leveling costs, PBMs have ratcheted up prices at multiple junctures to gain more profit.

The FTC’s investigation will focus on the six largest PBMs: CVS Caremark, Express Scripts, OptumRx, Humana, Prime Therapeutics, and MedImpact Healthcare Systems. CVS Caremark is owned by CVS, Express Scripts is owned by Cigna, and OptumRx is owned by UnitedHealth. The companies will have 90 days to respond to the commission’s official request for information.

Some of the information the FTC plans to ask about includes how the companies may be pushing patients toward using PBM-owned pharmacies and how rebates affect insurers’ formularies and the cost of drugs for patients.

The purchase or establishment of PBMs by the largest insurance companies – known as vertical integration – makes it nearly impossible for outsiders to determine what’s really causing price increases for prescription drugs. “The black box of secretive contracts and monies changing hands between manufacturers and PBMs has grown quite large since the Department of Justice and the FTC allowed the big three PBMs to be part of the three largest health insurance companies,” Madelaine A. Feldman, MD, a rheumatologist at the Rheumatology Group, New Orleans, and president of the Coalition of State Rheumatology Organizations, told this news organization.

A version of this article first appeared on Medscape.com.

Evidence summary

Surgical repair: Re-injury risk goes down, complications risk goes up

A 2021 network meta-analysis including 38 RCTs (N = 2480) reported outcomes in patients ages 18 and older with acute Achilles tendon rupture (AATR) and 3 or more months of follow-up.¹ A significant increase in re-rupture rate was shown in patients who underwent nonoperative vs open repair (risk ratio [RR] = 2.41; 95% CI, 1.12-5.18). There was a significant decrease in wound-related complications in nonoperative vs open-repair patients (RR = 0.23; 95% CI, 0.06-0.88). There was also a significant difference in incidence of sural nerve injury in nonoperative vs open repair (RR = 0.27; 95% CI, 0.08-0.94). There were no significant differences in return to sport between open repair and nonoperative repair (RR = 0.62; 95% CI, 0.22-1.77). Insufficient data were reported to calculate the number needed to treat (NNT) and number needed to harm (NNH) for these outcomes.

Additionally, the authors looked at traditional standard rehabilitation and accelerated functional rehabilitation in both the operative and the nonoperative setting. The type of rehabilitation program did not have a significant impact on complications of re-rupture, wound, or sural nerve injury.

The included studies had an overall low risk of publication bias based on Begg’s funnel plot test (Pr > |z| = 0.86). The highest risk was performance bias, as neither the participants nor personnel were blinded to treatment in 71% of the studies.

Functional outcomes are similar for surgical vs nonoperative repair

In a 2019 meta-analysis of 9 RCTs (N = 822), adults ages 18 and older with AATR and a minimum of 12 months’ follow-up were randomized to either operative or nonoperative repair. There was a decreased rate of rupture with surgical repair and an associated increased rate of complications (ie, superficial wound infections and nerve injury). However, there was no significant difference in Physical Activity Scale (PAS) score between the 2 groups (mean difference, –0.05; 95% CI, –0.37 to 0.27).² With surgical intervention, the NNT for Achilles tendon re-rupture was 15, and the NNH for superficial wound infection and nerve injury, respectively, were 22 and 28. Limitations of the study included different operative techniques and rehab protocols, which may have affected the results of the included studies.

Large data sets with consistent results show that nonoperative treatment of Achilles tendon rupture is an excellent option.

A third meta-analysis consisted of 10 RCTs and 19 observational studies (N = 15,862) with patients ages 16 years and older treated operatively vs nonoperatively. Function and return-to-activity rates in both the short term (≤ 1 year) and long term (> 1 year) were evaluated using the Achilles tendon Total Rupture Score (ATRS).³ Surgical management was associated with decreased re-rupture rates but increased complication rates. However, when the analysis was limited to studies using accelerated functional rehabilitation programs, there was no significant difference in re-rupture rate (RR = 0.26 to 1.37; P = .23). Only 1 observational study found a statistically significant difference in short-term functional outcomes favoring operative management, and no studies found a significant difference in long-term functional outcomes. These functional outcomes were not pooled for statistical analysis due to high interrater variability of the ATRS.

An RCT showed equal “customer satisfaction”

One RCT randomized 61 patients to either surgical or nonsurgical management and followed them for a mean of 15.7 years.⁴ Patient-reported outcomes of function, symptoms, and impact on daily life were measured using various surveys. There was no statistically significant difference in the function and impact on daily life after treatment according to the Short Musculoskeletal Function Assessment or the ATRS (P = .289 and .313, respectively). When assessed using the Net Promoter Score (a single-question metric used in consumer industry to assess whether an individual would recommend the product to others), there was no statistical significance for the patients to recommend one treatment over another: 79% of operatively managed patients vs 87% of nonoperatively managed patients would recommend their treatment to others (P = .225).

Recommendations from others

The American College of Foot and Ankle Surgeons consensus statement finds no difference between operative and nonoperative management with regard to complications, functional outcome, and return to activity long term, when looking at available Level 1 evidence.⁵ They do acknowledge that although some Level III studies suggest operative intervention will return high-­functioning patients to full activity sooner, there should be discussion regarding the risks and complications of both operative and nonoperative management. Patients with increased risk factors for postoperative complications (diabetes, obesity, cigarette smoking) should have special considerations regarding the decision to operate.

Editor’s takeaway

Large data sets with consistent results show that nonoperative treatment of Achilles tendon rupture is an excellent option. However, we cannot say if it is better or worse than operative treatment, because both options have advantages and disadvantages. One must weigh the alternatives with individual patient preferences and circumstances.

Evidence summary

Surgical repair: Re-injury risk goes down, complications risk goes up

A 2021 network meta-analysis including 38 RCTs (N = 2480) reported outcomes in patients ages 18 and older with acute Achilles tendon rupture (AATR) and 3 or more months of follow-up.¹ A significant increase in re-rupture rate was shown in patients who underwent nonoperative vs open repair (risk ratio [RR] = 2.41; 95% CI, 1.12-5.18). There was a significant decrease in wound-related complications in nonoperative vs open-repair patients (RR = 0.23; 95% CI, 0.06-0.88). There was also a significant difference in incidence of sural nerve injury in nonoperative vs open repair (RR = 0.27; 95% CI, 0.08-0.94). There were no significant differences in return to sport between open repair and nonoperative repair (RR = 0.62; 95% CI, 0.22-1.77). Insufficient data were reported to calculate the number needed to treat (NNT) and number needed to harm (NNH) for these outcomes.

Additionally, the authors looked at traditional standard rehabilitation and accelerated functional rehabilitation in both the operative and the nonoperative setting. The type of rehabilitation program did not have a significant impact on complications of re-rupture, wound, or sural nerve injury.

The included studies had an overall low risk of publication bias based on Begg’s funnel plot test (Pr > |z| = 0.86). The highest risk was performance bias, as neither the participants nor personnel were blinded to treatment in 71% of the studies.

Functional outcomes are similar for surgical vs nonoperative repair

In a 2019 meta-analysis of 9 RCTs (N = 822), adults ages 18 and older with AATR and a minimum of 12 months’ follow-up were randomized to either operative or nonoperative repair. There was a decreased rate of rupture with surgical repair and an associated increased rate of complications (ie, superficial wound infections and nerve injury). However, there was no significant difference in Physical Activity Scale (PAS) score between the 2 groups (mean difference, –0.05; 95% CI, –0.37 to 0.27).² With surgical intervention, the NNT for Achilles tendon re-rupture was 15, and the NNH for superficial wound infection and nerve injury, respectively, were 22 and 28. Limitations of the study included different operative techniques and rehab protocols, which may have affected the results of the included studies.

Large data sets with consistent results show that nonoperative treatment of Achilles tendon rupture is an excellent option.

A third meta-analysis consisted of 10 RCTs and 19 observational studies (N = 15,862) with patients ages 16 years and older treated operatively vs nonoperatively. Function and return-to-activity rates in both the short term (≤ 1 year) and long term (> 1 year) were evaluated using the Achilles tendon Total Rupture Score (ATRS).³ Surgical management was associated with decreased re-rupture rates but increased complication rates. However, when the analysis was limited to studies using accelerated functional rehabilitation programs, there was no significant difference in re-rupture rate (RR = 0.26 to 1.37; P = .23). Only 1 observational study found a statistically significant difference in short-term functional outcomes favoring operative management, and no studies found a significant difference in long-term functional outcomes. These functional outcomes were not pooled for statistical analysis due to high interrater variability of the ATRS.

An RCT showed equal “customer satisfaction”

One RCT randomized 61 patients to either surgical or nonsurgical management and followed them for a mean of 15.7 years.⁴ Patient-reported outcomes of function, symptoms, and impact on daily life were measured using various surveys. There was no statistically significant difference in the function and impact on daily life after treatment according to the Short Musculoskeletal Function Assessment or the ATRS (P = .289 and .313, respectively). When assessed using the Net Promoter Score (a single-question metric used in consumer industry to assess whether an individual would recommend the product to others), there was no statistical significance for the patients to recommend one treatment over another: 79% of operatively managed patients vs 87% of nonoperatively managed patients would recommend their treatment to others (P = .225).

Recommendations from others

The American College of Foot and Ankle Surgeons consensus statement finds no difference between operative and nonoperative management with regard to complications, functional outcome, and return to activity long term, when looking at available Level 1 evidence.⁵ They do acknowledge that although some Level III studies suggest operative intervention will return high-­functioning patients to full activity sooner, there should be discussion regarding the risks and complications of both operative and nonoperative management. Patients with increased risk factors for postoperative complications (diabetes, obesity, cigarette smoking) should have special considerations regarding the decision to operate.

Editor’s takeaway

Large data sets with consistent results show that nonoperative treatment of Achilles tendon rupture is an excellent option. However, we cannot say if it is better or worse than operative treatment, because both options have advantages and disadvantages. One must weigh the alternatives with individual patient preferences and circumstances.

Evidence summary

Surgical repair: Re-injury risk goes down, complications risk goes up

A 2021 network meta-analysis including 38 RCTs (N = 2480) reported outcomes in patients ages 18 and older with acute Achilles tendon rupture (AATR) and 3 or more months of follow-up.¹ A significant increase in re-rupture rate was shown in patients who underwent nonoperative vs open repair (risk ratio [RR] = 2.41; 95% CI, 1.12-5.18). There was a significant decrease in wound-related complications in nonoperative vs open-repair patients (RR = 0.23; 95% CI, 0.06-0.88). There was also a significant difference in incidence of sural nerve injury in nonoperative vs open repair (RR = 0.27; 95% CI, 0.08-0.94). There were no significant differences in return to sport between open repair and nonoperative repair (RR = 0.62; 95% CI, 0.22-1.77). Insufficient data were reported to calculate the number needed to treat (NNT) and number needed to harm (NNH) for these outcomes.

Additionally, the authors looked at traditional standard rehabilitation and accelerated functional rehabilitation in both the operative and the nonoperative setting. The type of rehabilitation program did not have a significant impact on complications of re-rupture, wound, or sural nerve injury.

The included studies had an overall low risk of publication bias based on Begg’s funnel plot test (Pr > |z| = 0.86). The highest risk was performance bias, as neither the participants nor personnel were blinded to treatment in 71% of the studies.

Functional outcomes are similar for surgical vs nonoperative repair

In a 2019 meta-analysis of 9 RCTs (N = 822), adults ages 18 and older with AATR and a minimum of 12 months’ follow-up were randomized to either operative or nonoperative repair. There was a decreased rate of rupture with surgical repair and an associated increased rate of complications (ie, superficial wound infections and nerve injury). However, there was no significant difference in Physical Activity Scale (PAS) score between the 2 groups (mean difference, –0.05; 95% CI, –0.37 to 0.27).² With surgical intervention, the NNT for Achilles tendon re-rupture was 15, and the NNH for superficial wound infection and nerve injury, respectively, were 22 and 28. Limitations of the study included different operative techniques and rehab protocols, which may have affected the results of the included studies.

Large data sets with consistent results show that nonoperative treatment of Achilles tendon rupture is an excellent option.

A third meta-analysis consisted of 10 RCTs and 19 observational studies (N = 15,862) with patients ages 16 years and older treated operatively vs nonoperatively. Function and return-to-activity rates in both the short term (≤ 1 year) and long term (> 1 year) were evaluated using the Achilles tendon Total Rupture Score (ATRS).³ Surgical management was associated with decreased re-rupture rates but increased complication rates. However, when the analysis was limited to studies using accelerated functional rehabilitation programs, there was no significant difference in re-rupture rate (RR = 0.26 to 1.37; P = .23). Only 1 observational study found a statistically significant difference in short-term functional outcomes favoring operative management, and no studies found a significant difference in long-term functional outcomes. These functional outcomes were not pooled for statistical analysis due to high interrater variability of the ATRS.

An RCT showed equal “customer satisfaction”

One RCT randomized 61 patients to either surgical or nonsurgical management and followed them for a mean of 15.7 years.⁴ Patient-reported outcomes of function, symptoms, and impact on daily life were measured using various surveys. There was no statistically significant difference in the function and impact on daily life after treatment according to the Short Musculoskeletal Function Assessment or the ATRS (P = .289 and .313, respectively). When assessed using the Net Promoter Score (a single-question metric used in consumer industry to assess whether an individual would recommend the product to others), there was no statistical significance for the patients to recommend one treatment over another: 79% of operatively managed patients vs 87% of nonoperatively managed patients would recommend their treatment to others (P = .225).

Recommendations from others

The American College of Foot and Ankle Surgeons consensus statement finds no difference between operative and nonoperative management with regard to complications, functional outcome, and return to activity long term, when looking at available Level 1 evidence.⁵ They do acknowledge that although some Level III studies suggest operative intervention will return high-­functioning patients to full activity sooner, there should be discussion regarding the risks and complications of both operative and nonoperative management. Patients with increased risk factors for postoperative complications (diabetes, obesity, cigarette smoking) should have special considerations regarding the decision to operate.

Editor’s takeaway

Large data sets with consistent results show that nonoperative treatment of Achilles tendon rupture is an excellent option. However, we cannot say if it is better or worse than operative treatment, because both options have advantages and disadvantages. One must weigh the alternatives with individual patient preferences and circumstances.

THE CASE

Declan M*, a 42-year-old man, presents as a new patient for general medical care. One year ago, he sustained a severe frontal traumatic brain injury (TBI) when he was hit by a car while crossing a street. He developed a subdural hematoma and was in a coma for 6 days. He also had fractured ribs and a fractured left foot. When he regained consciousness, he had posttraumatic amnesia. He also had executive function deficits and memory difficulties, so a guardian was appointed.

Mr. M no longer works as an auto mechanic, a career he once greatly enjoyed. Mr. M’s guardian reports that recently, Mr. M has lost interest in activities he’d previously enjoyed, is frequently irritable, has poor sleep, is socially isolated, and is spending increasing amounts of time at home. When his new primary care physician (PCP) enters the examining room, Mr. M is seated in a chair with his arms folded across his chest. He states that he is “fine” and just needs to “get a doctor.”

● HOW WOULD YOU PROCEED WITH THIS PATIENT?

*This patient is an amalgam of patients for whom the author has provided care.

TBI ranges from mild to severe and can produce a number of profound effects that are a direct—or indirect—result of the physical injury.¹ The location and the severity of the injury affect symptoms.² Even mild TBI can cause impairment, and severe TBI can lead to broad cognitive, behavioral, and physical difficulties. As numbers of TBI cases increase globally, primary care providers need to recognize the symptoms and assess accordingly.¹ The Acute Concussion Evaluation (ACE; Physician/Clinician Office Version) facilitates a structured evaluation for patients presenting with possible TBI symptoms. It can easily be accessed on the Centers for Disease Control and Prevention website.³

Direct effects of TBI include impulsivity, depression, reduced frustration tolerance, reduced motivation, low awareness, and insomnia and other sleep difficulties.^4,5 Depression may also result indirectly from, or be exacerbated by, new posttraumatic limitations and lifestyle changes as well as loss of career and community.⁴ Both direct and indirect depression often manifest as feelings of hopelessness and worthlessness and a lack of interest in once enjoyable activities. Depression can worsen other TBI sequelae such as difficulty concentrating, lack of initiation, flat affect, irritability, reduced independence, reduced functional performance, loss of inhibition, and physical pain.⁶

Suicidality in TBI is a chronic concern. Assess for its presence no matter how long ago the TBI occurred.

Nationwide, most mental health concerns continue to be addressed in the primary care setting.⁷ Individuals with TBI experience major depression at a rate 5 to 6 times higher than those in the general population, with a prevalence rate of 45%.⁸

Suicide. The subject of suicide must be explored with survivors of TBI; evidence suggests a correlation between TBI, depression, and increased risk for suicide.⁹ Among those who have TBI, as many as 22% experience suicidal ideation; the risk of suicide in survivors of severe TBI is 3 to 4 times the risk in the general population.¹⁰ Additionally, suicidality in this context appears to be a chronic concern; therefore, carefully assess for its presence no matter how long ago the TBI occurred.¹⁰

Additional TBI-associated health concerns

Grief and loss. We so often focus on death as the only cause for grief, but grief can occur for other types of loss, as well. Individuals with TBI often experience a radical negative change in self-concept after their injury, which is associated with feelings of grief.¹¹ Helping patients recognize that they are grieving the loss of the person they once were can help set a framework for their experience.

Continue to: Relationship loss

Relationship loss. Many people with TBI lose close relationships.¹² This can be due to life changes such as job loss, loss of function or ability to do previously enjoyed activities, or personality changes. These relationship losses can affect a person profoundly.¹² Going forward, they may have difficulty trusting others, for example.

Existential issues. Many people with TBI also find that cognitive deficits prevent them from engaging in formerly meaningful work. For example, Mr. M lost his longstanding career as an auto mechanic and therefore part of his identity. Not being able to find purpose and meaning can be a strong contributor to coping difficulties in those with TBI.¹³

Chronic pain. More than half of people with TBI experience chronic pain. Headaches are the most common pain condition among all TBI survivors.¹⁴

Substance use disorders. The directionality of substance use disorders and TBI is not always clear; however, most evidence suggests that substance abuse is highly prevalent, premorbid, and often a contributing factor in TBI (eg, car accidents).¹⁵ Alcohol abuse is the most common risk factor, followed by drug abuse.¹⁶ Substance abuse may be exacerbated after TBI when it becomes a coping mechanism under worsening stressors; additionally, executive function deficits or other neurologic problems may result in poor decision-making with regard to substance use.¹⁵ While substance abuse may decline in the immediate post-TBI period, it can return to pre-injury levels within a year.¹⁷

Selective serotonin reuptake inhibitors may help

Few studies have explored the efficacy of antidepressant medication in TBI survivors. In a controlled study of patients with TBI, Fann and colleagues¹⁸ found no significant improvement in depression symptoms between sertraline and a placebo. However, they did note some possibilities for this lack of significance: socially isolated TBI survivors in the placebo group may have demonstrated improvement in depression symptoms because of increased social interaction; members of both the sertraline and placebo groups had many psychosocial difficulties; and the study had a relatively small sample size. Worth noting: Subjects given sertraline did demonstrate improvement in information processing.

Continue to: Other research has found...

Other research has found that sertraline improved both depression and quality of life for men with post-TBI depression.¹⁹ In a ­meta-analysis of 4 studies, Paraschakis and Katsanos²⁰ found that sertraline demonstrated a “trend toward significance” in the treatment of depression among patients with TBI. Silverberg and Panenka²¹ argue that selective serotonin reuptake inhibitors should be used as first-line treatment for depression in survivors of TBI. They note that in non-randomized studies, treatment effects with antidepressants are significant. Additionally, patients who do not respond to the first antidepressant prescribed will often respond to adjunctive or different medications. Finally, they argue that depression measures can capture symptoms related to the physical brain injury, in addition to symptoms of depression, thus confounding results.

THE CASE

Mr. M’s chart showed that he was not taking any medication and that he had no history of substance abuse or tobacco use. He refused to fill out the Patient Health Questionnaire (PHQ)-2. His guardian said that Mr. M was spending much of his time at home, and that he used to be an avid painter and guitar player but had not engaged in either activity for months. Furthermore, Mr. M used to enjoy working out but did so rarely now.

During the interview, the PCP was careful to make eye contact with Mr. M as well as his guardian, thereby making sure Mr. M was part of the conversation about his care. Pacing of questions was deliberate and unhurried; a return visit would be scheduled to further explore any concerns not covered in this visit. This collaborative, inclusive, patient-centered approach to the clinical interview seemed to place Mr. M at ease. When his guardian said he thought Mr. M was depressed, Mr. M agreed. Although Mr. M still refused to fill out the PHQ-2, he was now willing to answer questions about depression. He acknowledged that he was feeling hopeless and took little pleasure in activities he used to enjoy, thereby indicating a positive screen for depression.

The PCP opted to read the PHQ-9 questions aloud, and Mr. M agreed with most of the items but strongly denied suicidal ideation, citing his religious faith.

The PCP determined that Mr. M’s depression was likely a combination of the direct and indirect effects of his TBI. A quantitative estimate based on Mr. M’s report yielded a PHQ-9 score of 17, indicating moderately severe depression.

Continue to: In addition to building rapport...

In addition to building rapport, careful listening garnered important information about Mr. M. For example, until his accident and subsequent depression, Mr. M had long prioritized his physical health through diet and exercise. He followed a vegetarian diet but recently had little appetite and was eating one microwaveable meal a day. He had an irregular sleep schedule and struggled with insomnia. He lost his closest long-term relationship after his accident due to difficulties with affect regulation. He also lost his job as he could no longer cognitively handle the tasks required.

Hearing Mr. M’s story provided the opportunity to customize education about self-management skills including regular diet, exercise, and sleep hygiene. Due to limited visit time, the PCP elected to use this first visit to focus on sleep and depression. As cognitive behavioral therapy (CBT) for insomnia is first-line treatment for both primary insomnia and insomnia due to a medical condition such as TBI,⁵ a sleep aid was not prescribed. Fortunately, the clinic psychologist who offered CBT was able to join the interview to meet Mr. M and explain the treatment.

Mr. M expressed some initial reluctance to try an antidepressant. However, acknowledging he “just hasn’t been the same” since his TBI, he agreed to a prescription for sertraline and said he hoped it could make him “more like [he] was.”

RETURN VISIT

Four weeks after Mr. M began taking sertraline and participating in weekly CBT sessions, he returned for a follow-up visit with his PCP. He had a noticeably brighter affect, and his guardian reported that he had been playing the guitar again. Mr. M said that he had more energy as a result of improved sleep and mood, and that he felt like his “thinking was clearer.” Mr. M noted that he never thought he would meet with a psychologist but was finding CBT for insomnia helpful.

Patients who do not respond to the first antidepressant prescribed will often respond to adjunctive or different medications.

The psychologist’s notes proposed a treatment plan that would also include targeted grief and existential therapies to address Mr. M’s sudden life changes. At this visit, Mr. M admitted that his reading comprehension and speed were negatively affected by the accident and said this is why he did not wish to fill out the PHQ-2. But he was again willing to have the PHQ-9 questions read to him with his guardian’s support. Results showed a score of 6, indicating mild depression.

A follow-up appointment with Mr. M was scheduled for 6 weeks later, and the team was confident he was getting the behavioral and mental health support he needed through medication and therapy.

CORRESPONDENCE
Elizabeth Imbesi, PhD, VA Ann Arbor Healthcare System, 2215 Fuller Road, Ann Arbor, MI 48105; [email protected]

THE CASE

Declan M*, a 42-year-old man, presents as a new patient for general medical care. One year ago, he sustained a severe frontal traumatic brain injury (TBI) when he was hit by a car while crossing a street. He developed a subdural hematoma and was in a coma for 6 days. He also had fractured ribs and a fractured left foot. When he regained consciousness, he had posttraumatic amnesia. He also had executive function deficits and memory difficulties, so a guardian was appointed.

Mr. M no longer works as an auto mechanic, a career he once greatly enjoyed. Mr. M’s guardian reports that recently, Mr. M has lost interest in activities he’d previously enjoyed, is frequently irritable, has poor sleep, is socially isolated, and is spending increasing amounts of time at home. When his new primary care physician (PCP) enters the examining room, Mr. M is seated in a chair with his arms folded across his chest. He states that he is “fine” and just needs to “get a doctor.”

● HOW WOULD YOU PROCEED WITH THIS PATIENT?

*This patient is an amalgam of patients for whom the author has provided care.

TBI ranges from mild to severe and can produce a number of profound effects that are a direct—or indirect—result of the physical injury.¹ The location and the severity of the injury affect symptoms.² Even mild TBI can cause impairment, and severe TBI can lead to broad cognitive, behavioral, and physical difficulties. As numbers of TBI cases increase globally, primary care providers need to recognize the symptoms and assess accordingly.¹ The Acute Concussion Evaluation (ACE; Physician/Clinician Office Version) facilitates a structured evaluation for patients presenting with possible TBI symptoms. It can easily be accessed on the Centers for Disease Control and Prevention website.³

Direct effects of TBI include impulsivity, depression, reduced frustration tolerance, reduced motivation, low awareness, and insomnia and other sleep difficulties.^4,5 Depression may also result indirectly from, or be exacerbated by, new posttraumatic limitations and lifestyle changes as well as loss of career and community.⁴ Both direct and indirect depression often manifest as feelings of hopelessness and worthlessness and a lack of interest in once enjoyable activities. Depression can worsen other TBI sequelae such as difficulty concentrating, lack of initiation, flat affect, irritability, reduced independence, reduced functional performance, loss of inhibition, and physical pain.⁶

Suicidality in TBI is a chronic concern. Assess for its presence no matter how long ago the TBI occurred.

Nationwide, most mental health concerns continue to be addressed in the primary care setting.⁷ Individuals with TBI experience major depression at a rate 5 to 6 times higher than those in the general population, with a prevalence rate of 45%.⁸

Suicide. The subject of suicide must be explored with survivors of TBI; evidence suggests a correlation between TBI, depression, and increased risk for suicide.⁹ Among those who have TBI, as many as 22% experience suicidal ideation; the risk of suicide in survivors of severe TBI is 3 to 4 times the risk in the general population.¹⁰ Additionally, suicidality in this context appears to be a chronic concern; therefore, carefully assess for its presence no matter how long ago the TBI occurred.¹⁰

Additional TBI-associated health concerns

Grief and loss. We so often focus on death as the only cause for grief, but grief can occur for other types of loss, as well. Individuals with TBI often experience a radical negative change in self-concept after their injury, which is associated with feelings of grief.¹¹ Helping patients recognize that they are grieving the loss of the person they once were can help set a framework for their experience.

Continue to: Relationship loss

Relationship loss. Many people with TBI lose close relationships.¹² This can be due to life changes such as job loss, loss of function or ability to do previously enjoyed activities, or personality changes. These relationship losses can affect a person profoundly.¹² Going forward, they may have difficulty trusting others, for example.

Existential issues. Many people with TBI also find that cognitive deficits prevent them from engaging in formerly meaningful work. For example, Mr. M lost his longstanding career as an auto mechanic and therefore part of his identity. Not being able to find purpose and meaning can be a strong contributor to coping difficulties in those with TBI.¹³

Chronic pain. More than half of people with TBI experience chronic pain. Headaches are the most common pain condition among all TBI survivors.¹⁴

Substance use disorders. The directionality of substance use disorders and TBI is not always clear; however, most evidence suggests that substance abuse is highly prevalent, premorbid, and often a contributing factor in TBI (eg, car accidents).¹⁵ Alcohol abuse is the most common risk factor, followed by drug abuse.¹⁶ Substance abuse may be exacerbated after TBI when it becomes a coping mechanism under worsening stressors; additionally, executive function deficits or other neurologic problems may result in poor decision-making with regard to substance use.¹⁵ While substance abuse may decline in the immediate post-TBI period, it can return to pre-injury levels within a year.¹⁷

Selective serotonin reuptake inhibitors may help

Few studies have explored the efficacy of antidepressant medication in TBI survivors. In a controlled study of patients with TBI, Fann and colleagues¹⁸ found no significant improvement in depression symptoms between sertraline and a placebo. However, they did note some possibilities for this lack of significance: socially isolated TBI survivors in the placebo group may have demonstrated improvement in depression symptoms because of increased social interaction; members of both the sertraline and placebo groups had many psychosocial difficulties; and the study had a relatively small sample size. Worth noting: Subjects given sertraline did demonstrate improvement in information processing.

Continue to: Other research has found...

Other research has found that sertraline improved both depression and quality of life for men with post-TBI depression.¹⁹ In a ­meta-analysis of 4 studies, Paraschakis and Katsanos²⁰ found that sertraline demonstrated a “trend toward significance” in the treatment of depression among patients with TBI. Silverberg and Panenka²¹ argue that selective serotonin reuptake inhibitors should be used as first-line treatment for depression in survivors of TBI. They note that in non-randomized studies, treatment effects with antidepressants are significant. Additionally, patients who do not respond to the first antidepressant prescribed will often respond to adjunctive or different medications. Finally, they argue that depression measures can capture symptoms related to the physical brain injury, in addition to symptoms of depression, thus confounding results.

THE CASE

Mr. M’s chart showed that he was not taking any medication and that he had no history of substance abuse or tobacco use. He refused to fill out the Patient Health Questionnaire (PHQ)-2. His guardian said that Mr. M was spending much of his time at home, and that he used to be an avid painter and guitar player but had not engaged in either activity for months. Furthermore, Mr. M used to enjoy working out but did so rarely now.

During the interview, the PCP was careful to make eye contact with Mr. M as well as his guardian, thereby making sure Mr. M was part of the conversation about his care. Pacing of questions was deliberate and unhurried; a return visit would be scheduled to further explore any concerns not covered in this visit. This collaborative, inclusive, patient-centered approach to the clinical interview seemed to place Mr. M at ease. When his guardian said he thought Mr. M was depressed, Mr. M agreed. Although Mr. M still refused to fill out the PHQ-2, he was now willing to answer questions about depression. He acknowledged that he was feeling hopeless and took little pleasure in activities he used to enjoy, thereby indicating a positive screen for depression.

The PCP opted to read the PHQ-9 questions aloud, and Mr. M agreed with most of the items but strongly denied suicidal ideation, citing his religious faith.

The PCP determined that Mr. M’s depression was likely a combination of the direct and indirect effects of his TBI. A quantitative estimate based on Mr. M’s report yielded a PHQ-9 score of 17, indicating moderately severe depression.

Continue to: In addition to building rapport...

In addition to building rapport, careful listening garnered important information about Mr. M. For example, until his accident and subsequent depression, Mr. M had long prioritized his physical health through diet and exercise. He followed a vegetarian diet but recently had little appetite and was eating one microwaveable meal a day. He had an irregular sleep schedule and struggled with insomnia. He lost his closest long-term relationship after his accident due to difficulties with affect regulation. He also lost his job as he could no longer cognitively handle the tasks required.

Hearing Mr. M’s story provided the opportunity to customize education about self-management skills including regular diet, exercise, and sleep hygiene. Due to limited visit time, the PCP elected to use this first visit to focus on sleep and depression. As cognitive behavioral therapy (CBT) for insomnia is first-line treatment for both primary insomnia and insomnia due to a medical condition such as TBI,⁵ a sleep aid was not prescribed. Fortunately, the clinic psychologist who offered CBT was able to join the interview to meet Mr. M and explain the treatment.

Mr. M expressed some initial reluctance to try an antidepressant. However, acknowledging he “just hasn’t been the same” since his TBI, he agreed to a prescription for sertraline and said he hoped it could make him “more like [he] was.”

RETURN VISIT

Four weeks after Mr. M began taking sertraline and participating in weekly CBT sessions, he returned for a follow-up visit with his PCP. He had a noticeably brighter affect, and his guardian reported that he had been playing the guitar again. Mr. M said that he had more energy as a result of improved sleep and mood, and that he felt like his “thinking was clearer.” Mr. M noted that he never thought he would meet with a psychologist but was finding CBT for insomnia helpful.

Patients who do not respond to the first antidepressant prescribed will often respond to adjunctive or different medications.

The psychologist’s notes proposed a treatment plan that would also include targeted grief and existential therapies to address Mr. M’s sudden life changes. At this visit, Mr. M admitted that his reading comprehension and speed were negatively affected by the accident and said this is why he did not wish to fill out the PHQ-2. But he was again willing to have the PHQ-9 questions read to him with his guardian’s support. Results showed a score of 6, indicating mild depression.

A follow-up appointment with Mr. M was scheduled for 6 weeks later, and the team was confident he was getting the behavioral and mental health support he needed through medication and therapy.

CORRESPONDENCE
Elizabeth Imbesi, PhD, VA Ann Arbor Healthcare System, 2215 Fuller Road, Ann Arbor, MI 48105; [email protected]

THE CASE

Declan M*, a 42-year-old man, presents as a new patient for general medical care. One year ago, he sustained a severe frontal traumatic brain injury (TBI) when he was hit by a car while crossing a street. He developed a subdural hematoma and was in a coma for 6 days. He also had fractured ribs and a fractured left foot. When he regained consciousness, he had posttraumatic amnesia. He also had executive function deficits and memory difficulties, so a guardian was appointed.

Mr. M no longer works as an auto mechanic, a career he once greatly enjoyed. Mr. M’s guardian reports that recently, Mr. M has lost interest in activities he’d previously enjoyed, is frequently irritable, has poor sleep, is socially isolated, and is spending increasing amounts of time at home. When his new primary care physician (PCP) enters the examining room, Mr. M is seated in a chair with his arms folded across his chest. He states that he is “fine” and just needs to “get a doctor.”

● HOW WOULD YOU PROCEED WITH THIS PATIENT?

*This patient is an amalgam of patients for whom the author has provided care.

TBI ranges from mild to severe and can produce a number of profound effects that are a direct—or indirect—result of the physical injury.¹ The location and the severity of the injury affect symptoms.² Even mild TBI can cause impairment, and severe TBI can lead to broad cognitive, behavioral, and physical difficulties. As numbers of TBI cases increase globally, primary care providers need to recognize the symptoms and assess accordingly.¹ The Acute Concussion Evaluation (ACE; Physician/Clinician Office Version) facilitates a structured evaluation for patients presenting with possible TBI symptoms. It can easily be accessed on the Centers for Disease Control and Prevention website.³

Direct effects of TBI include impulsivity, depression, reduced frustration tolerance, reduced motivation, low awareness, and insomnia and other sleep difficulties.^4,5 Depression may also result indirectly from, or be exacerbated by, new posttraumatic limitations and lifestyle changes as well as loss of career and community.⁴ Both direct and indirect depression often manifest as feelings of hopelessness and worthlessness and a lack of interest in once enjoyable activities. Depression can worsen other TBI sequelae such as difficulty concentrating, lack of initiation, flat affect, irritability, reduced independence, reduced functional performance, loss of inhibition, and physical pain.⁶

Suicidality in TBI is a chronic concern. Assess for its presence no matter how long ago the TBI occurred.

Nationwide, most mental health concerns continue to be addressed in the primary care setting.⁷ Individuals with TBI experience major depression at a rate 5 to 6 times higher than those in the general population, with a prevalence rate of 45%.⁸

Suicide. The subject of suicide must be explored with survivors of TBI; evidence suggests a correlation between TBI, depression, and increased risk for suicide.⁹ Among those who have TBI, as many as 22% experience suicidal ideation; the risk of suicide in survivors of severe TBI is 3 to 4 times the risk in the general population.¹⁰ Additionally, suicidality in this context appears to be a chronic concern; therefore, carefully assess for its presence no matter how long ago the TBI occurred.¹⁰

Additional TBI-associated health concerns

Grief and loss. We so often focus on death as the only cause for grief, but grief can occur for other types of loss, as well. Individuals with TBI often experience a radical negative change in self-concept after their injury, which is associated with feelings of grief.¹¹ Helping patients recognize that they are grieving the loss of the person they once were can help set a framework for their experience.

Continue to: Relationship loss

Relationship loss. Many people with TBI lose close relationships.¹² This can be due to life changes such as job loss, loss of function or ability to do previously enjoyed activities, or personality changes. These relationship losses can affect a person profoundly.¹² Going forward, they may have difficulty trusting others, for example.

Existential issues. Many people with TBI also find that cognitive deficits prevent them from engaging in formerly meaningful work. For example, Mr. M lost his longstanding career as an auto mechanic and therefore part of his identity. Not being able to find purpose and meaning can be a strong contributor to coping difficulties in those with TBI.¹³

Chronic pain. More than half of people with TBI experience chronic pain. Headaches are the most common pain condition among all TBI survivors.¹⁴

Substance use disorders. The directionality of substance use disorders and TBI is not always clear; however, most evidence suggests that substance abuse is highly prevalent, premorbid, and often a contributing factor in TBI (eg, car accidents).¹⁵ Alcohol abuse is the most common risk factor, followed by drug abuse.¹⁶ Substance abuse may be exacerbated after TBI when it becomes a coping mechanism under worsening stressors; additionally, executive function deficits or other neurologic problems may result in poor decision-making with regard to substance use.¹⁵ While substance abuse may decline in the immediate post-TBI period, it can return to pre-injury levels within a year.¹⁷

Selective serotonin reuptake inhibitors may help

Few studies have explored the efficacy of antidepressant medication in TBI survivors. In a controlled study of patients with TBI, Fann and colleagues¹⁸ found no significant improvement in depression symptoms between sertraline and a placebo. However, they did note some possibilities for this lack of significance: socially isolated TBI survivors in the placebo group may have demonstrated improvement in depression symptoms because of increased social interaction; members of both the sertraline and placebo groups had many psychosocial difficulties; and the study had a relatively small sample size. Worth noting: Subjects given sertraline did demonstrate improvement in information processing.

Continue to: Other research has found...

Other research has found that sertraline improved both depression and quality of life for men with post-TBI depression.¹⁹ In a ­meta-analysis of 4 studies, Paraschakis and Katsanos²⁰ found that sertraline demonstrated a “trend toward significance” in the treatment of depression among patients with TBI. Silverberg and Panenka²¹ argue that selective serotonin reuptake inhibitors should be used as first-line treatment for depression in survivors of TBI. They note that in non-randomized studies, treatment effects with antidepressants are significant. Additionally, patients who do not respond to the first antidepressant prescribed will often respond to adjunctive or different medications. Finally, they argue that depression measures can capture symptoms related to the physical brain injury, in addition to symptoms of depression, thus confounding results.

THE CASE

Mr. M’s chart showed that he was not taking any medication and that he had no history of substance abuse or tobacco use. He refused to fill out the Patient Health Questionnaire (PHQ)-2. His guardian said that Mr. M was spending much of his time at home, and that he used to be an avid painter and guitar player but had not engaged in either activity for months. Furthermore, Mr. M used to enjoy working out but did so rarely now.

During the interview, the PCP was careful to make eye contact with Mr. M as well as his guardian, thereby making sure Mr. M was part of the conversation about his care. Pacing of questions was deliberate and unhurried; a return visit would be scheduled to further explore any concerns not covered in this visit. This collaborative, inclusive, patient-centered approach to the clinical interview seemed to place Mr. M at ease. When his guardian said he thought Mr. M was depressed, Mr. M agreed. Although Mr. M still refused to fill out the PHQ-2, he was now willing to answer questions about depression. He acknowledged that he was feeling hopeless and took little pleasure in activities he used to enjoy, thereby indicating a positive screen for depression.

The PCP opted to read the PHQ-9 questions aloud, and Mr. M agreed with most of the items but strongly denied suicidal ideation, citing his religious faith.

The PCP determined that Mr. M’s depression was likely a combination of the direct and indirect effects of his TBI. A quantitative estimate based on Mr. M’s report yielded a PHQ-9 score of 17, indicating moderately severe depression.

Continue to: In addition to building rapport...

In addition to building rapport, careful listening garnered important information about Mr. M. For example, until his accident and subsequent depression, Mr. M had long prioritized his physical health through diet and exercise. He followed a vegetarian diet but recently had little appetite and was eating one microwaveable meal a day. He had an irregular sleep schedule and struggled with insomnia. He lost his closest long-term relationship after his accident due to difficulties with affect regulation. He also lost his job as he could no longer cognitively handle the tasks required.

Hearing Mr. M’s story provided the opportunity to customize education about self-management skills including regular diet, exercise, and sleep hygiene. Due to limited visit time, the PCP elected to use this first visit to focus on sleep and depression. As cognitive behavioral therapy (CBT) for insomnia is first-line treatment for both primary insomnia and insomnia due to a medical condition such as TBI,⁵ a sleep aid was not prescribed. Fortunately, the clinic psychologist who offered CBT was able to join the interview to meet Mr. M and explain the treatment.

Mr. M expressed some initial reluctance to try an antidepressant. However, acknowledging he “just hasn’t been the same” since his TBI, he agreed to a prescription for sertraline and said he hoped it could make him “more like [he] was.”

RETURN VISIT

Four weeks after Mr. M began taking sertraline and participating in weekly CBT sessions, he returned for a follow-up visit with his PCP. He had a noticeably brighter affect, and his guardian reported that he had been playing the guitar again. Mr. M said that he had more energy as a result of improved sleep and mood, and that he felt like his “thinking was clearer.” Mr. M noted that he never thought he would meet with a psychologist but was finding CBT for insomnia helpful.

Patients who do not respond to the first antidepressant prescribed will often respond to adjunctive or different medications.

The psychologist’s notes proposed a treatment plan that would also include targeted grief and existential therapies to address Mr. M’s sudden life changes. At this visit, Mr. M admitted that his reading comprehension and speed were negatively affected by the accident and said this is why he did not wish to fill out the PHQ-2. But he was again willing to have the PHQ-9 questions read to him with his guardian’s support. Results showed a score of 6, indicating mild depression.

A follow-up appointment with Mr. M was scheduled for 6 weeks later, and the team was confident he was getting the behavioral and mental health support he needed through medication and therapy.

CORRESPONDENCE
Elizabeth Imbesi, PhD, VA Ann Arbor Healthcare System, 2215 Fuller Road, Ann Arbor, MI 48105; [email protected]

CHARLOTTE, N.C. – Erratic sleep patterns over years or even decades, along with a patient’s age and history of depression, may be harbingers of cognitive impairment later in life, an analysis of decades of data from a large sleep study has found.

“What we were a little surprised to find in this model was that sleep duration, whether short, long or average, was not significant, but the sleep variability – the change in sleep across those time measurements—was significantly impacting the incidence of cognitive impairment,” Samantha Keil, PhD, a postdoctoral fellow at the University of Washington, Seattle, reported at the at the annual meeting of the Associated Professional Sleep Societies.

The researchers analyzed sleep and cognition data collected over decades on 1,104 adults who participated in the Seattle Longitudinal Study. Study participants ranged from age 55 to over 100, with almost 80% of the study cohort aged 65 and older.

The Seattle Longitudinal Study first started gathering data in the 1950s. Participants in the study cohort underwent an extensive cognitive battery, which was added to the study in 1984 and gathered every 5-7 years, and completed a health behavioral questionnaire (HBQ), which was added in 1993 and administered every 3-5 years, Dr. Keil said. The HBQ included a question on average nightly sleep duration.

The study used a multivariable Cox proportional hazard regression model to evaluate the overall effect of average sleep duration and changes in sleep duration over time on cognitive impairment. Covariates used in the model included apolipoprotein E4 (APOE4) genotype, gender, years of education, ethnicity, and depression.

Dr. Keil said the model found, as expected, that the  demographic variables of education, APOE status, and depression were significantly associated with cognitive impairment (hazard ratios of 1.11; 95% confidence interval [CI], 1.02-1.21; P = .01; and 2.08; 95% CI, 1.31-3.31; P < .005; and 1.08; 95% CI, 1.04-1.13; P < .005, respectively). Importantly, when evaluating the duration, change and variability of sleep, the researchers found that increased sleep variability was significantly associated with cognitive impairment (HR, 3.15; 95% CI, 1.69-5.87; P < .005).  

Under this analysis, “sleep variability over time and not median sleep duration was associated with cognitive impairment,” she said. When sleep variability was added into the model, it improved the concordance score – a value that reflects the ability of a model to predict an outcome better than random chance – from .63 to .73 (a value of .5 indicates the model is no better at predicting an outcome than a random chance model; a value of .7 or greater indicates a good model).

Identification of sleep variability as a sleep pattern of interest in longitudinal studies is important, Dr. Keil said, because simply evaluating mean or median sleep duration across time might not account for a subject’s variable sleep phenotype. Most importantly, further evaluation of sleep variability with a linear regression prediction analysis (F statistic 8.796, P < .0001, adjusted R-squared .235) found that increased age, depression, and sleep variability significantly predicted cognitive impairment 10 years downstream. “Longitudinal sleep variability is perhaps for the first time being reported as significantly associated with the development of downstream cognitive impairment,” Dr. Keil said.

What makes this study unique, Dr. Keil said in an interview, is that it used self-reported longitudinal data gathered at 3- to 5-year intervals for up to 25 years, allowing for the assessment of variation of sleep duration across this entire time frame. “If you could use that shift in sleep duration as a point of therapeutic intervention, that would be really exciting,” she said.

Future research will evaluate how sleep variability and cognitive function are impacted by other variables gathered in the Seattle Longitudinal Study over the years, including factors such as diabetes and hypertension status, diet, alcohol and tobacco use, and marital and family status. Follow-up studies will be investigating the impact of sleep variability on neuropathologic disease progression and lymphatic system impairment, Dr. Keil said.
 

A newer approach

By linking sleep variability and daytime functioning, the study employs a “newer approach,” said Joseph M. Dzierzewski, PhD, director of behavioral medicine concentration in the department of psychology at Virginia Commonwealth University in Richmond. “While some previous work has examined night-to-night fluctuation in various sleep characteristics and cognitive functioning, what differentiates the present study from these previous works is the duration of the investigation,” he said. The “richness of data” in the Seattle Longitudinal Study and how it tracks sleep and cognition over years make it “quite unique and novel.”

Future studies, he said, should be deliberate in how they evaluate sleep and neurocognitive function across years. “Disentangling short-term moment-to-moment and day-to-day fluctuation, which may be more reversible in nature, from long-term, enduring month-to-month or year-to-year fluctuation, which may be more permanent, will be important for continuing to advance our understanding of these complex phenomena,” Dr. Dzierzewski said. “An additional important area of future investigation would be to continue the hunt for a common biological factor underpinning both sleep variability and Alzheimer’s disease.” That, he said, may help identify potential intervention targets.

Dr. Keil and Dr. Dzierzewski have no relevant disclosures.

CHARLOTTE, N.C. – Erratic sleep patterns over years or even decades, along with a patient’s age and history of depression, may be harbingers of cognitive impairment later in life, an analysis of decades of data from a large sleep study has found.

“What we were a little surprised to find in this model was that sleep duration, whether short, long or average, was not significant, but the sleep variability – the change in sleep across those time measurements—was significantly impacting the incidence of cognitive impairment,” Samantha Keil, PhD, a postdoctoral fellow at the University of Washington, Seattle, reported at the at the annual meeting of the Associated Professional Sleep Societies.

The researchers analyzed sleep and cognition data collected over decades on 1,104 adults who participated in the Seattle Longitudinal Study. Study participants ranged from age 55 to over 100, with almost 80% of the study cohort aged 65 and older.

The Seattle Longitudinal Study first started gathering data in the 1950s. Participants in the study cohort underwent an extensive cognitive battery, which was added to the study in 1984 and gathered every 5-7 years, and completed a health behavioral questionnaire (HBQ), which was added in 1993 and administered every 3-5 years, Dr. Keil said. The HBQ included a question on average nightly sleep duration.

The study used a multivariable Cox proportional hazard regression model to evaluate the overall effect of average sleep duration and changes in sleep duration over time on cognitive impairment. Covariates used in the model included apolipoprotein E4 (APOE4) genotype, gender, years of education, ethnicity, and depression.

Dr. Keil said the model found, as expected, that the  demographic variables of education, APOE status, and depression were significantly associated with cognitive impairment (hazard ratios of 1.11; 95% confidence interval [CI], 1.02-1.21; P = .01; and 2.08; 95% CI, 1.31-3.31; P < .005; and 1.08; 95% CI, 1.04-1.13; P < .005, respectively). Importantly, when evaluating the duration, change and variability of sleep, the researchers found that increased sleep variability was significantly associated with cognitive impairment (HR, 3.15; 95% CI, 1.69-5.87; P < .005).  

Under this analysis, “sleep variability over time and not median sleep duration was associated with cognitive impairment,” she said. When sleep variability was added into the model, it improved the concordance score – a value that reflects the ability of a model to predict an outcome better than random chance – from .63 to .73 (a value of .5 indicates the model is no better at predicting an outcome than a random chance model; a value of .7 or greater indicates a good model).

Identification of sleep variability as a sleep pattern of interest in longitudinal studies is important, Dr. Keil said, because simply evaluating mean or median sleep duration across time might not account for a subject’s variable sleep phenotype. Most importantly, further evaluation of sleep variability with a linear regression prediction analysis (F statistic 8.796, P < .0001, adjusted R-squared .235) found that increased age, depression, and sleep variability significantly predicted cognitive impairment 10 years downstream. “Longitudinal sleep variability is perhaps for the first time being reported as significantly associated with the development of downstream cognitive impairment,” Dr. Keil said.

What makes this study unique, Dr. Keil said in an interview, is that it used self-reported longitudinal data gathered at 3- to 5-year intervals for up to 25 years, allowing for the assessment of variation of sleep duration across this entire time frame. “If you could use that shift in sleep duration as a point of therapeutic intervention, that would be really exciting,” she said.

Future research will evaluate how sleep variability and cognitive function are impacted by other variables gathered in the Seattle Longitudinal Study over the years, including factors such as diabetes and hypertension status, diet, alcohol and tobacco use, and marital and family status. Follow-up studies will be investigating the impact of sleep variability on neuropathologic disease progression and lymphatic system impairment, Dr. Keil said.
 

A newer approach

By linking sleep variability and daytime functioning, the study employs a “newer approach,” said Joseph M. Dzierzewski, PhD, director of behavioral medicine concentration in the department of psychology at Virginia Commonwealth University in Richmond. “While some previous work has examined night-to-night fluctuation in various sleep characteristics and cognitive functioning, what differentiates the present study from these previous works is the duration of the investigation,” he said. The “richness of data” in the Seattle Longitudinal Study and how it tracks sleep and cognition over years make it “quite unique and novel.”

Future studies, he said, should be deliberate in how they evaluate sleep and neurocognitive function across years. “Disentangling short-term moment-to-moment and day-to-day fluctuation, which may be more reversible in nature, from long-term, enduring month-to-month or year-to-year fluctuation, which may be more permanent, will be important for continuing to advance our understanding of these complex phenomena,” Dr. Dzierzewski said. “An additional important area of future investigation would be to continue the hunt for a common biological factor underpinning both sleep variability and Alzheimer’s disease.” That, he said, may help identify potential intervention targets.

Dr. Keil and Dr. Dzierzewski have no relevant disclosures.

CHARLOTTE, N.C. – Erratic sleep patterns over years or even decades, along with a patient’s age and history of depression, may be harbingers of cognitive impairment later in life, an analysis of decades of data from a large sleep study has found.

“What we were a little surprised to find in this model was that sleep duration, whether short, long or average, was not significant, but the sleep variability – the change in sleep across those time measurements—was significantly impacting the incidence of cognitive impairment,” Samantha Keil, PhD, a postdoctoral fellow at the University of Washington, Seattle, reported at the at the annual meeting of the Associated Professional Sleep Societies.

The researchers analyzed sleep and cognition data collected over decades on 1,104 adults who participated in the Seattle Longitudinal Study. Study participants ranged from age 55 to over 100, with almost 80% of the study cohort aged 65 and older.

The Seattle Longitudinal Study first started gathering data in the 1950s. Participants in the study cohort underwent an extensive cognitive battery, which was added to the study in 1984 and gathered every 5-7 years, and completed a health behavioral questionnaire (HBQ), which was added in 1993 and administered every 3-5 years, Dr. Keil said. The HBQ included a question on average nightly sleep duration.

The study used a multivariable Cox proportional hazard regression model to evaluate the overall effect of average sleep duration and changes in sleep duration over time on cognitive impairment. Covariates used in the model included apolipoprotein E4 (APOE4) genotype, gender, years of education, ethnicity, and depression.

Dr. Keil said the model found, as expected, that the  demographic variables of education, APOE status, and depression were significantly associated with cognitive impairment (hazard ratios of 1.11; 95% confidence interval [CI], 1.02-1.21; P = .01; and 2.08; 95% CI, 1.31-3.31; P < .005; and 1.08; 95% CI, 1.04-1.13; P < .005, respectively). Importantly, when evaluating the duration, change and variability of sleep, the researchers found that increased sleep variability was significantly associated with cognitive impairment (HR, 3.15; 95% CI, 1.69-5.87; P < .005).  

Under this analysis, “sleep variability over time and not median sleep duration was associated with cognitive impairment,” she said. When sleep variability was added into the model, it improved the concordance score – a value that reflects the ability of a model to predict an outcome better than random chance – from .63 to .73 (a value of .5 indicates the model is no better at predicting an outcome than a random chance model; a value of .7 or greater indicates a good model).

Identification of sleep variability as a sleep pattern of interest in longitudinal studies is important, Dr. Keil said, because simply evaluating mean or median sleep duration across time might not account for a subject’s variable sleep phenotype. Most importantly, further evaluation of sleep variability with a linear regression prediction analysis (F statistic 8.796, P < .0001, adjusted R-squared .235) found that increased age, depression, and sleep variability significantly predicted cognitive impairment 10 years downstream. “Longitudinal sleep variability is perhaps for the first time being reported as significantly associated with the development of downstream cognitive impairment,” Dr. Keil said.

What makes this study unique, Dr. Keil said in an interview, is that it used self-reported longitudinal data gathered at 3- to 5-year intervals for up to 25 years, allowing for the assessment of variation of sleep duration across this entire time frame. “If you could use that shift in sleep duration as a point of therapeutic intervention, that would be really exciting,” she said.

Future research will evaluate how sleep variability and cognitive function are impacted by other variables gathered in the Seattle Longitudinal Study over the years, including factors such as diabetes and hypertension status, diet, alcohol and tobacco use, and marital and family status. Follow-up studies will be investigating the impact of sleep variability on neuropathologic disease progression and lymphatic system impairment, Dr. Keil said.
 

A newer approach

By linking sleep variability and daytime functioning, the study employs a “newer approach,” said Joseph M. Dzierzewski, PhD, director of behavioral medicine concentration in the department of psychology at Virginia Commonwealth University in Richmond. “While some previous work has examined night-to-night fluctuation in various sleep characteristics and cognitive functioning, what differentiates the present study from these previous works is the duration of the investigation,” he said. The “richness of data” in the Seattle Longitudinal Study and how it tracks sleep and cognition over years make it “quite unique and novel.”

Future studies, he said, should be deliberate in how they evaluate sleep and neurocognitive function across years. “Disentangling short-term moment-to-moment and day-to-day fluctuation, which may be more reversible in nature, from long-term, enduring month-to-month or year-to-year fluctuation, which may be more permanent, will be important for continuing to advance our understanding of these complex phenomena,” Dr. Dzierzewski said. “An additional important area of future investigation would be to continue the hunt for a common biological factor underpinning both sleep variability and Alzheimer’s disease.” That, he said, may help identify potential intervention targets.

Dr. Keil and Dr. Dzierzewski have no relevant disclosures.

Boston Children’s Hospital led the list of 10 children’s hospitals across the United States named to the Best Children’s Hospitals Honor Roll for 2022-2023, issued by U.S. News & World Report.

The 16th annual Best Children’s Hospitals rankings were published on June 14.

Rounding out the top 10 on the Honor Roll were Children’s Hospital of Philadelphia; Texas Children’s Hospital, Houston; Cincinnati Children’s Hospital Medical Center; Children’s Hospital Los Angeles; Children’s Hospital Colorado, Aurora; Children’s National Hospital, Washington, D.C.; Nationwide Children’s Hospital, Columbus, Ohio; UPMC Children’s Hospital of Pittsburgh; and Lucile Packard Children’s Hospital, Palo Alto, Calif.

The Honor Roll hospitals were chosen based on being highly ranked in multiple specialties, such as cancer, cardiology, and orthopedics.

For the second time, the rankings included top hospitals not only in each state, but also in seven multistate regions. The goal of the regional rankings is to help families identify the high-quality pediatric care centers closest to them, according to the U.S. News press release accompanying the rankings.

The top-ranked hospitals for the seven regions were Children’s Hospital Los Angeles (Pacific); Children’s Hospital Colorado, Aurora (Rocky Mountains); Texas Children’s Hospital, Houston (Southwest); Children’s Healthcare of Atlanta and Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, Tenn. (tie for Southeast); Cincinnati Children’s Hospital Medical Center (Midwest); Children’s Hospital of Philadelphia (Mid-Atlantic); and Boston Children’s Hospital (New England).

The 2022-2023 U.S. News rankings identify the top 50 centers across the United States in each of 10 pediatric specialties: cancer, cardiology/ heart surgery, diabetes/endocrinology, gastroenterology/gastrointestinal surgery, neonatology, nephrology, neurology/neurosurgery, orthopedics, pulmonology/lung surgery, and urology.

For the 2022-2023 rankings, U.S. News requested medical data and other information from 200 pediatric facilities across the United States; 119 responded and were evaluated in at least one specialty, and 90 were ranked in one or more specialties.

Approximately one-third of each hospital’s score was based on outcomes such as survival, infections, and surgical complications (although outcomes counted for 38.3% of scores for cardiology and heart surgery). Approximately 13% of the score was based on reputation/expert opinion, determined by an annual survey of experts in the 10 specialties (8% of scores for cardiology and heart surgery), and nearly 60% was based on patient safety, excellence, and family centeredness, according to a statement from U.S. News.

“The Best Children’s Hospitals rankings spotlight hospitals that excel in specialized care, offering parents and their pediatricians a helpful starting point in choosing the facility that’s best for their child,” said Ben Harder, chief of health analysis and managing editor at U.S. News, in a press release accompanying the rankings.

Also new to the ranking system this year was a measure to assess hospitals’ efforts to improve equity of care and to promote diversity and inclusion, which accounts for 2% of each hospital’s score in each specialty, according to U.S. News.

Boston Children’s Hospital led the list of 10 children’s hospitals across the United States named to the Best Children’s Hospitals Honor Roll for 2022-2023, issued by U.S. News & World Report.

The 16th annual Best Children’s Hospitals rankings were published on June 14.

Rounding out the top 10 on the Honor Roll were Children’s Hospital of Philadelphia; Texas Children’s Hospital, Houston; Cincinnati Children’s Hospital Medical Center; Children’s Hospital Los Angeles; Children’s Hospital Colorado, Aurora; Children’s National Hospital, Washington, D.C.; Nationwide Children’s Hospital, Columbus, Ohio; UPMC Children’s Hospital of Pittsburgh; and Lucile Packard Children’s Hospital, Palo Alto, Calif.

The Honor Roll hospitals were chosen based on being highly ranked in multiple specialties, such as cancer, cardiology, and orthopedics.

For the second time, the rankings included top hospitals not only in each state, but also in seven multistate regions. The goal of the regional rankings is to help families identify the high-quality pediatric care centers closest to them, according to the U.S. News press release accompanying the rankings.

The top-ranked hospitals for the seven regions were Children’s Hospital Los Angeles (Pacific); Children’s Hospital Colorado, Aurora (Rocky Mountains); Texas Children’s Hospital, Houston (Southwest); Children’s Healthcare of Atlanta and Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, Tenn. (tie for Southeast); Cincinnati Children’s Hospital Medical Center (Midwest); Children’s Hospital of Philadelphia (Mid-Atlantic); and Boston Children’s Hospital (New England).

The 2022-2023 U.S. News rankings identify the top 50 centers across the United States in each of 10 pediatric specialties: cancer, cardiology/ heart surgery, diabetes/endocrinology, gastroenterology/gastrointestinal surgery, neonatology, nephrology, neurology/neurosurgery, orthopedics, pulmonology/lung surgery, and urology.

For the 2022-2023 rankings, U.S. News requested medical data and other information from 200 pediatric facilities across the United States; 119 responded and were evaluated in at least one specialty, and 90 were ranked in one or more specialties.

Approximately one-third of each hospital’s score was based on outcomes such as survival, infections, and surgical complications (although outcomes counted for 38.3% of scores for cardiology and heart surgery). Approximately 13% of the score was based on reputation/expert opinion, determined by an annual survey of experts in the 10 specialties (8% of scores for cardiology and heart surgery), and nearly 60% was based on patient safety, excellence, and family centeredness, according to a statement from U.S. News.

“The Best Children’s Hospitals rankings spotlight hospitals that excel in specialized care, offering parents and their pediatricians a helpful starting point in choosing the facility that’s best for their child,” said Ben Harder, chief of health analysis and managing editor at U.S. News, in a press release accompanying the rankings.

Also new to the ranking system this year was a measure to assess hospitals’ efforts to improve equity of care and to promote diversity and inclusion, which accounts for 2% of each hospital’s score in each specialty, according to U.S. News.

Boston Children’s Hospital led the list of 10 children’s hospitals across the United States named to the Best Children’s Hospitals Honor Roll for 2022-2023, issued by U.S. News & World Report.

The 16th annual Best Children’s Hospitals rankings were published on June 14.

Rounding out the top 10 on the Honor Roll were Children’s Hospital of Philadelphia; Texas Children’s Hospital, Houston; Cincinnati Children’s Hospital Medical Center; Children’s Hospital Los Angeles; Children’s Hospital Colorado, Aurora; Children’s National Hospital, Washington, D.C.; Nationwide Children’s Hospital, Columbus, Ohio; UPMC Children’s Hospital of Pittsburgh; and Lucile Packard Children’s Hospital, Palo Alto, Calif.

The Honor Roll hospitals were chosen based on being highly ranked in multiple specialties, such as cancer, cardiology, and orthopedics.

For the second time, the rankings included top hospitals not only in each state, but also in seven multistate regions. The goal of the regional rankings is to help families identify the high-quality pediatric care centers closest to them, according to the U.S. News press release accompanying the rankings.

The top-ranked hospitals for the seven regions were Children’s Hospital Los Angeles (Pacific); Children’s Hospital Colorado, Aurora (Rocky Mountains); Texas Children’s Hospital, Houston (Southwest); Children’s Healthcare of Atlanta and Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, Tenn. (tie for Southeast); Cincinnati Children’s Hospital Medical Center (Midwest); Children’s Hospital of Philadelphia (Mid-Atlantic); and Boston Children’s Hospital (New England).

The 2022-2023 U.S. News rankings identify the top 50 centers across the United States in each of 10 pediatric specialties: cancer, cardiology/ heart surgery, diabetes/endocrinology, gastroenterology/gastrointestinal surgery, neonatology, nephrology, neurology/neurosurgery, orthopedics, pulmonology/lung surgery, and urology.

For the 2022-2023 rankings, U.S. News requested medical data and other information from 200 pediatric facilities across the United States; 119 responded and were evaluated in at least one specialty, and 90 were ranked in one or more specialties.

Approximately one-third of each hospital’s score was based on outcomes such as survival, infections, and surgical complications (although outcomes counted for 38.3% of scores for cardiology and heart surgery). Approximately 13% of the score was based on reputation/expert opinion, determined by an annual survey of experts in the 10 specialties (8% of scores for cardiology and heart surgery), and nearly 60% was based on patient safety, excellence, and family centeredness, according to a statement from U.S. News.

“The Best Children’s Hospitals rankings spotlight hospitals that excel in specialized care, offering parents and their pediatricians a helpful starting point in choosing the facility that’s best for their child,” said Ben Harder, chief of health analysis and managing editor at U.S. News, in a press release accompanying the rankings.

Also new to the ranking system this year was a measure to assess hospitals’ efforts to improve equity of care and to promote diversity and inclusion, which accounts for 2% of each hospital’s score in each specialty, according to U.S. News.

The development of depression after a rheumatoid arthritis diagnosis increased the risk for death “more than sixfold” when compared with having no depression at diagnosis, according to Danish researchers.

Cumulative mortality at 10 years was approximately 37% in patients with comorbid RA and depression versus around 13.5% of RA patients with no depression, Jens Kristian Pedersen, MD, PhD, of Odense (Denmark) University Hospital–Svendborg Hospital and the department of clinical research at the University of Southern Denmark, also in Odense, reported at the annual European Congress of Rheumatology.

“According to [antidepressant] exposure status, the cumulative mortality followed two clearly different paths,” Dr. Pedersen said. “The mortality curves separated early and already within the first and second year of follow-up.”
 

RA, depression, and mortality

Rates of depression in patients with RA are high, Dr. Pedersen said, and while it’s previously been reported that their coexistence can increase mortality, this is the first time that the link has been investigated in a population newly diagnosed with RA.

In this study, Dr. Pedersen and collaborators wanted to look at the association in incident RA and defined depression as the first filling of an antidepressant prescription.

“Although antidepressants are used for different indications, we have recently described that in RA the most frequent indication for filling antidepressants is depression,” he explained. Moreover, that research found that “the frequency of filling coincides with the occurrence of depressive disorder previously reported in the scientific literature.”
 

Data sourced from multiple Danish registers

To examine the mortality risk associated with newly diagnosed RA and new-onset depression, Dr. Pedersen described how five different Danish registers were used.

First, data from the DANBIO register were used to identify patients with incident RA living in Denmark over a 10-year period ending in December 2018. Although perhaps widely known as a biologics register, DANBIO is required by the Danish National Board of Health to collect information on all patients with RA, regardless of their treatment.

Next, the Danish National Prescription Register and Danish National Patient Register were consulted to obtain data on patients who had a first prescription for antidepressant treatment and information on those who developed a diagnosis of depression. Demographic, vital status, and socioeconomic data were collated from the Danish Civil Registration System and Statistics Denmark databases.

To be sure they were looking at incident cases of RA and new cases of depression, the researchers excluded anyone with an existing prescription of antidepressants or methotrexate, or who had a confirmed diagnosis of either disorder 3 years prior to the index date of Jan. 1, 2008.

This meant that, from a total population of 18,000 patients in the DANBIO database, there were just over 11,000 who could be included in the analyses.

Overall, the median age at RA diagnosis was 61 years, two-thirds were female, and two-thirds had seropositive disease.

New-onset depression in incident RA

“During follow-up, about 10% filled a prescription of antidepressants,” said Dr. Pedersen, adding that there were 671 deaths, representing around 57,000 person-years at risk.

“The majority died from natural causes,” he said, although the cause of death was unknown in 30% of cases.

Comparing those who did and did not have a prescription for antidepressants, there were some differences in the age at which death occurred, the percentage of females to males, the presence of other comorbidities, and levels of higher education and income. These were all adjusted for in the analyses.

Adjusted hazard rate ratios were calculated to look at the mortality risk in patients who had antidepressant exposure. The highest HRR for mortality with antidepressant use was seen in patients aged 55 years or younger at 6.66, with the next highest HRRs being for male gender (3.70) and seropositive RA (3.45).

But HRRs for seronegative RA, female gender, and age 55-70 years or older than 75 years were all still around 3.0.
 

Depression definition questioned

“My only concern is about the definition of depression in your analysis,” said a member of the audience at the congress.

“You used antidepressant use as a proxy of depression diagnosis, but it might be that most or many patients have taken [medication] like duloxetine for pain control, and you are just seeing higher disease activity and more aggressive RA.”

Dr. Pedersen responded: “After the EULAR 2022 submission deadline, we reanalyzed our data using two other measures of depression.

“First, we use treatment with antidepressants with a positive indication of depression, according to the prescribing physician, and secondly, we used first diagnosis with depression according to ICD-10 Code F32 – ‘depressive episode after discharge from hospital as an outpatient,’ ” he said.

“All definitions end up with a hazard rate ratio of about three. So, in my opinion, it doesn’t matter whether you focus on one measure of depression or the other.”

David Isenberg, MD, FRCP, professor of rheumatology at University College London, wanted to know more about the antecedent history of depression and whether people who had been depressed maybe a decade or 2 decades before, were more likely to get RA.

That calculation has not been done, Dr. Pedersen said, adding that the study also can’t account for people who may have had recurrent depression. Depression treatment guidelines often recommend nonpharmacologic intervention in the first instance, “so we do not necessarily get the right picture of recurrent depression if we look further back.”

Pointing out that the sixfold increase in mortality was impressive, another delegate asked about whether it was because of a higher disease activity or joint damage and if the mortality risk might be lower in patients who are in remission.

“We don’t know that yet,” Dr. Pedersen answered. “We haven’t done the calculations, but there is the issue of residual confounding if we don’t take all relevant covariates into account. So, we need to do that calculation as well.”

The study was supported by the Danish Rheumatism Association. Dr. Pedersen had no conflicts of interest to disclose.
 

The development of depression after a rheumatoid arthritis diagnosis increased the risk for death “more than sixfold” when compared with having no depression at diagnosis, according to Danish researchers.

Cumulative mortality at 10 years was approximately 37% in patients with comorbid RA and depression versus around 13.5% of RA patients with no depression, Jens Kristian Pedersen, MD, PhD, of Odense (Denmark) University Hospital–Svendborg Hospital and the department of clinical research at the University of Southern Denmark, also in Odense, reported at the annual European Congress of Rheumatology.

“According to [antidepressant] exposure status, the cumulative mortality followed two clearly different paths,” Dr. Pedersen said. “The mortality curves separated early and already within the first and second year of follow-up.”
 

RA, depression, and mortality

Rates of depression in patients with RA are high, Dr. Pedersen said, and while it’s previously been reported that their coexistence can increase mortality, this is the first time that the link has been investigated in a population newly diagnosed with RA.

In this study, Dr. Pedersen and collaborators wanted to look at the association in incident RA and defined depression as the first filling of an antidepressant prescription.

“Although antidepressants are used for different indications, we have recently described that in RA the most frequent indication for filling antidepressants is depression,” he explained. Moreover, that research found that “the frequency of filling coincides with the occurrence of depressive disorder previously reported in the scientific literature.”
 

Data sourced from multiple Danish registers

To examine the mortality risk associated with newly diagnosed RA and new-onset depression, Dr. Pedersen described how five different Danish registers were used.

First, data from the DANBIO register were used to identify patients with incident RA living in Denmark over a 10-year period ending in December 2018. Although perhaps widely known as a biologics register, DANBIO is required by the Danish National Board of Health to collect information on all patients with RA, regardless of their treatment.

Next, the Danish National Prescription Register and Danish National Patient Register were consulted to obtain data on patients who had a first prescription for antidepressant treatment and information on those who developed a diagnosis of depression. Demographic, vital status, and socioeconomic data were collated from the Danish Civil Registration System and Statistics Denmark databases.

To be sure they were looking at incident cases of RA and new cases of depression, the researchers excluded anyone with an existing prescription of antidepressants or methotrexate, or who had a confirmed diagnosis of either disorder 3 years prior to the index date of Jan. 1, 2008.

This meant that, from a total population of 18,000 patients in the DANBIO database, there were just over 11,000 who could be included in the analyses.

Overall, the median age at RA diagnosis was 61 years, two-thirds were female, and two-thirds had seropositive disease.

New-onset depression in incident RA

“During follow-up, about 10% filled a prescription of antidepressants,” said Dr. Pedersen, adding that there were 671 deaths, representing around 57,000 person-years at risk.

“The majority died from natural causes,” he said, although the cause of death was unknown in 30% of cases.

Comparing those who did and did not have a prescription for antidepressants, there were some differences in the age at which death occurred, the percentage of females to males, the presence of other comorbidities, and levels of higher education and income. These were all adjusted for in the analyses.

Adjusted hazard rate ratios were calculated to look at the mortality risk in patients who had antidepressant exposure. The highest HRR for mortality with antidepressant use was seen in patients aged 55 years or younger at 6.66, with the next highest HRRs being for male gender (3.70) and seropositive RA (3.45).

But HRRs for seronegative RA, female gender, and age 55-70 years or older than 75 years were all still around 3.0.
 

Depression definition questioned

“My only concern is about the definition of depression in your analysis,” said a member of the audience at the congress.

“You used antidepressant use as a proxy of depression diagnosis, but it might be that most or many patients have taken [medication] like duloxetine for pain control, and you are just seeing higher disease activity and more aggressive RA.”

Dr. Pedersen responded: “After the EULAR 2022 submission deadline, we reanalyzed our data using two other measures of depression.

“First, we use treatment with antidepressants with a positive indication of depression, according to the prescribing physician, and secondly, we used first diagnosis with depression according to ICD-10 Code F32 – ‘depressive episode after discharge from hospital as an outpatient,’ ” he said.

“All definitions end up with a hazard rate ratio of about three. So, in my opinion, it doesn’t matter whether you focus on one measure of depression or the other.”

David Isenberg, MD, FRCP, professor of rheumatology at University College London, wanted to know more about the antecedent history of depression and whether people who had been depressed maybe a decade or 2 decades before, were more likely to get RA.

That calculation has not been done, Dr. Pedersen said, adding that the study also can’t account for people who may have had recurrent depression. Depression treatment guidelines often recommend nonpharmacologic intervention in the first instance, “so we do not necessarily get the right picture of recurrent depression if we look further back.”

Pointing out that the sixfold increase in mortality was impressive, another delegate asked about whether it was because of a higher disease activity or joint damage and if the mortality risk might be lower in patients who are in remission.

“We don’t know that yet,” Dr. Pedersen answered. “We haven’t done the calculations, but there is the issue of residual confounding if we don’t take all relevant covariates into account. So, we need to do that calculation as well.”

The study was supported by the Danish Rheumatism Association. Dr. Pedersen had no conflicts of interest to disclose.
 

The development of depression after a rheumatoid arthritis diagnosis increased the risk for death “more than sixfold” when compared with having no depression at diagnosis, according to Danish researchers.

Cumulative mortality at 10 years was approximately 37% in patients with comorbid RA and depression versus around 13.5% of RA patients with no depression, Jens Kristian Pedersen, MD, PhD, of Odense (Denmark) University Hospital–Svendborg Hospital and the department of clinical research at the University of Southern Denmark, also in Odense, reported at the annual European Congress of Rheumatology.

“According to [antidepressant] exposure status, the cumulative mortality followed two clearly different paths,” Dr. Pedersen said. “The mortality curves separated early and already within the first and second year of follow-up.”
 

RA, depression, and mortality

Rates of depression in patients with RA are high, Dr. Pedersen said, and while it’s previously been reported that their coexistence can increase mortality, this is the first time that the link has been investigated in a population newly diagnosed with RA.

In this study, Dr. Pedersen and collaborators wanted to look at the association in incident RA and defined depression as the first filling of an antidepressant prescription.

“Although antidepressants are used for different indications, we have recently described that in RA the most frequent indication for filling antidepressants is depression,” he explained. Moreover, that research found that “the frequency of filling coincides with the occurrence of depressive disorder previously reported in the scientific literature.”
 

Data sourced from multiple Danish registers

To examine the mortality risk associated with newly diagnosed RA and new-onset depression, Dr. Pedersen described how five different Danish registers were used.

First, data from the DANBIO register were used to identify patients with incident RA living in Denmark over a 10-year period ending in December 2018. Although perhaps widely known as a biologics register, DANBIO is required by the Danish National Board of Health to collect information on all patients with RA, regardless of their treatment.

Next, the Danish National Prescription Register and Danish National Patient Register were consulted to obtain data on patients who had a first prescription for antidepressant treatment and information on those who developed a diagnosis of depression. Demographic, vital status, and socioeconomic data were collated from the Danish Civil Registration System and Statistics Denmark databases.

To be sure they were looking at incident cases of RA and new cases of depression, the researchers excluded anyone with an existing prescription of antidepressants or methotrexate, or who had a confirmed diagnosis of either disorder 3 years prior to the index date of Jan. 1, 2008.

This meant that, from a total population of 18,000 patients in the DANBIO database, there were just over 11,000 who could be included in the analyses.

Overall, the median age at RA diagnosis was 61 years, two-thirds were female, and two-thirds had seropositive disease.

New-onset depression in incident RA

“During follow-up, about 10% filled a prescription of antidepressants,” said Dr. Pedersen, adding that there were 671 deaths, representing around 57,000 person-years at risk.

“The majority died from natural causes,” he said, although the cause of death was unknown in 30% of cases.

Comparing those who did and did not have a prescription for antidepressants, there were some differences in the age at which death occurred, the percentage of females to males, the presence of other comorbidities, and levels of higher education and income. These were all adjusted for in the analyses.

Adjusted hazard rate ratios were calculated to look at the mortality risk in patients who had antidepressant exposure. The highest HRR for mortality with antidepressant use was seen in patients aged 55 years or younger at 6.66, with the next highest HRRs being for male gender (3.70) and seropositive RA (3.45).

But HRRs for seronegative RA, female gender, and age 55-70 years or older than 75 years were all still around 3.0.
 

Depression definition questioned

“My only concern is about the definition of depression in your analysis,” said a member of the audience at the congress.

“You used antidepressant use as a proxy of depression diagnosis, but it might be that most or many patients have taken [medication] like duloxetine for pain control, and you are just seeing higher disease activity and more aggressive RA.”

Dr. Pedersen responded: “After the EULAR 2022 submission deadline, we reanalyzed our data using two other measures of depression.

“First, we use treatment with antidepressants with a positive indication of depression, according to the prescribing physician, and secondly, we used first diagnosis with depression according to ICD-10 Code F32 – ‘depressive episode after discharge from hospital as an outpatient,’ ” he said.

“All definitions end up with a hazard rate ratio of about three. So, in my opinion, it doesn’t matter whether you focus on one measure of depression or the other.”

David Isenberg, MD, FRCP, professor of rheumatology at University College London, wanted to know more about the antecedent history of depression and whether people who had been depressed maybe a decade or 2 decades before, were more likely to get RA.

That calculation has not been done, Dr. Pedersen said, adding that the study also can’t account for people who may have had recurrent depression. Depression treatment guidelines often recommend nonpharmacologic intervention in the first instance, “so we do not necessarily get the right picture of recurrent depression if we look further back.”

Pointing out that the sixfold increase in mortality was impressive, another delegate asked about whether it was because of a higher disease activity or joint damage and if the mortality risk might be lower in patients who are in remission.

“We don’t know that yet,” Dr. Pedersen answered. “We haven’t done the calculations, but there is the issue of residual confounding if we don’t take all relevant covariates into account. So, we need to do that calculation as well.”

The study was supported by the Danish Rheumatism Association. Dr. Pedersen had no conflicts of interest to disclose.
 

ILLUSTRATIVE CASE

A 35-year-old woman with no significant past medical history presents for follow-up of migraine. At the previous visit, she was prescribed sumatriptan for abortive therapy. However, she has been having significant adverse effect intolerance from the oral formulation, and the nasal formulation is cost prohibitive. What can you recommend as an alternative abortive therapy for this patient’s migraine?

Migraine is among the most common causes of disability worldwide, affecting more than 10% of the global population.² The prevalence of migraine is between 2.6% and 21.7% across multiple countries.³ On a scale of 0% to 100%, disability caused by migraine is 43.3%, comparable to the first 2 days after an acute myocardial infarction (42.2%) and severe dementia (43.8%).⁴

Abortive therapy for acute migraine includes nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, ergots, and antiemetics. However, these options are predominantly administered by mouth; non-oral formulations tend to be cost prohibitive and difficult to obtain.

Nausea and vomiting, common components of migraine (that are included in International Classification of Headache Disorders, 3rd edition [ICHD-3] criteria for migraine⁵) present obstacles to effective oral administration if experienced by the patient. In addition, for migraine refractory to first-line treatments, abortive options—including the recently approved calcitonin gene-related peptide (CGRP) receptor antagonists ubrogepant and rimegepant—are also cost prohibitive, potentially costing more than $1000 for 10 tablets (100 mg), depending on insurance coverage.⁶

Two oral beta-blockers, propranolol and timolol, are approved by the US Food and Drug Administration for migraine prophylaxis. Unfortunately, oral beta-blockers are ineffective for abortive treatment.⁷ Ophthalmic timolol is typically used in the treatment of glaucoma, but there have been case reports describing its benefits in acute migraine treatment.^8,9 In addition, ophthalmic timolol is far cheaper than medications such as ubrogepant.¹⁰ A 2014 case series of 7 patients discussed ophthalmic beta-blockers as an effective and possibly cheaper option for acute migraine treatment.⁸ A randomized, crossover, placebo-controlled pilot study of 198 migraine attacks in 10 participants using timolol eyedrops for abortive therapy found timolol was not significantly more effective than placebo.⁹ However, it was an underpowered pilot study, with a lack of masking and an imperfect placebo. The trial discussed here was a controlled, prospective study investigating topical beta-blockers for acute migraine treatment.

STUDY SUMMARY

Crossover study achieved primary endpoint in pain reduction

This randomized, single-center, double-masked, crossover trial compared timolol maleate ophthalmic solution 0.5% with placebo among 43 patients ages 12 or older presenting with a diagnosis of migraine based on ICHD-3 (beta) criteria. Patients were eligible if they had not taken any antimigraine medications for at least 1 month prior to the study and were excluded if they had taken systemic beta-blockers at baseline, or had asthma, bradyarrhythmias, or cardiac dysfunction.

Patients were randomized 1:1 to treatment with timolol maleate 0.5% eyedrops or placebo. At the earliest onset of migraine, patients used 1 drop of timolol maleate 0.5% or placebo in each eye; if they experienced no relief after 10 minutes, they used a second drop or matching placebo. Patients were instructed to score their headache pain on a 10-point scale prior to using the eyedrops and then again 20 minutes after treatment. If a patient had migraine with aura, they were asked to use the eyedrops at the onset of the aura but measure their score at headache onset. If no headaches developed within 20 minutes of the aura, the episode was not included for analysis. All patients were permitted to use their standard oral rescue medication if no relief occurred after 20 minutes of pain onset.

Continue to: The groups were observed...

The groups were observed for 3 months and then followed for a 1-month washout period, during which they received no study medications. The groups were then crossed over to the other treatment and were observed for another 3 months. The primary outcome was a reduction in pain score by 4 or more points, or to 0 on a 10-point pain scale, 20 minutes after treatment. The secondary outcome was nonuse of oral rescue medication.

The primary outcome was achieved in 233 of 284 (82%) timolol-treated migraines, compared to 38 of 271 (14%) placebo-treated migraines.

Forty-three patients were included in a modified intention-to-treat analysis. The primary outcome was achieved in 233 of 284 (82%) timolol-treated migraines, compared to 38 of 271 (14%) placebo-treated migraines (percentage difference = 68 percentage points; 95% CI, 62-74 percentage points; P < .001). The mean pain score at the onset of migraine attacks was 6.01 for those treated with timolol and 5.93 for those treated with placebo. Patients treated with timolol had a reduction in pain of 5.98 points, compared with 0.93 points after using placebo (difference = 5.05; 95% CI, 4.19-5.91). No attacks included in the data required oral rescue medications, and there were no systemic adverse effects from the timolol eyedrops.

WHAT’S NEW

Evidence of benefit as abortive therapy for acute migraine

This randomized controlled trial (RCT) showed evidence to support timolol maleate ophthalmic solution 0.5% vs placebo for treatment of acute migraine by significantly reducing pain when taken at the onset of an acute migraine attack.

CAVEATS

Single-center trial, measuring limited response time

The generalizability of this RCT is limited because it was a single-center trial with a study population from a single region in India. It is unknown whether pain relief, adverse effects, or adherence would differ for the global population. Additionally, only migraines with headache were included in the analysis, limiting non-headache migraine subgroup-directed treatment. Also, this trial evaluated only the response to treatment at 20 minutes, and it is unknown if pain response continued for several hours. Headaches that began more than 20 minutes after the onset of aura were not evaluated.

CHALLENGES TO IMPLEMENTATION

Timolol’s systemic adverse effects require caution

Systemic beta-blocker effects (eg, bradycardia, hypotension, drowsiness, and bronchospasm) from topical timolol have been reported. Caution should be used when prescribing timolol for patients with current cardiovascular and pulmonary conditions. 

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 35-year-old woman with no significant past medical history presents for follow-up of migraine. At the previous visit, she was prescribed sumatriptan for abortive therapy. However, she has been having significant adverse effect intolerance from the oral formulation, and the nasal formulation is cost prohibitive. What can you recommend as an alternative abortive therapy for this patient’s migraine?

Migraine is among the most common causes of disability worldwide, affecting more than 10% of the global population.² The prevalence of migraine is between 2.6% and 21.7% across multiple countries.³ On a scale of 0% to 100%, disability caused by migraine is 43.3%, comparable to the first 2 days after an acute myocardial infarction (42.2%) and severe dementia (43.8%).⁴

Abortive therapy for acute migraine includes nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, ergots, and antiemetics. However, these options are predominantly administered by mouth; non-oral formulations tend to be cost prohibitive and difficult to obtain.

Nausea and vomiting, common components of migraine (that are included in International Classification of Headache Disorders, 3rd edition [ICHD-3] criteria for migraine⁵) present obstacles to effective oral administration if experienced by the patient. In addition, for migraine refractory to first-line treatments, abortive options—including the recently approved calcitonin gene-related peptide (CGRP) receptor antagonists ubrogepant and rimegepant—are also cost prohibitive, potentially costing more than $1000 for 10 tablets (100 mg), depending on insurance coverage.⁶

Two oral beta-blockers, propranolol and timolol, are approved by the US Food and Drug Administration for migraine prophylaxis. Unfortunately, oral beta-blockers are ineffective for abortive treatment.⁷ Ophthalmic timolol is typically used in the treatment of glaucoma, but there have been case reports describing its benefits in acute migraine treatment.^8,9 In addition, ophthalmic timolol is far cheaper than medications such as ubrogepant.¹⁰ A 2014 case series of 7 patients discussed ophthalmic beta-blockers as an effective and possibly cheaper option for acute migraine treatment.⁸ A randomized, crossover, placebo-controlled pilot study of 198 migraine attacks in 10 participants using timolol eyedrops for abortive therapy found timolol was not significantly more effective than placebo.⁹ However, it was an underpowered pilot study, with a lack of masking and an imperfect placebo. The trial discussed here was a controlled, prospective study investigating topical beta-blockers for acute migraine treatment.

STUDY SUMMARY

Crossover study achieved primary endpoint in pain reduction

This randomized, single-center, double-masked, crossover trial compared timolol maleate ophthalmic solution 0.5% with placebo among 43 patients ages 12 or older presenting with a diagnosis of migraine based on ICHD-3 (beta) criteria. Patients were eligible if they had not taken any antimigraine medications for at least 1 month prior to the study and were excluded if they had taken systemic beta-blockers at baseline, or had asthma, bradyarrhythmias, or cardiac dysfunction.

Patients were randomized 1:1 to treatment with timolol maleate 0.5% eyedrops or placebo. At the earliest onset of migraine, patients used 1 drop of timolol maleate 0.5% or placebo in each eye; if they experienced no relief after 10 minutes, they used a second drop or matching placebo. Patients were instructed to score their headache pain on a 10-point scale prior to using the eyedrops and then again 20 minutes after treatment. If a patient had migraine with aura, they were asked to use the eyedrops at the onset of the aura but measure their score at headache onset. If no headaches developed within 20 minutes of the aura, the episode was not included for analysis. All patients were permitted to use their standard oral rescue medication if no relief occurred after 20 minutes of pain onset.

Continue to: The groups were observed...

The groups were observed for 3 months and then followed for a 1-month washout period, during which they received no study medications. The groups were then crossed over to the other treatment and were observed for another 3 months. The primary outcome was a reduction in pain score by 4 or more points, or to 0 on a 10-point pain scale, 20 minutes after treatment. The secondary outcome was nonuse of oral rescue medication.

The primary outcome was achieved in 233 of 284 (82%) timolol-treated migraines, compared to 38 of 271 (14%) placebo-treated migraines.

Forty-three patients were included in a modified intention-to-treat analysis. The primary outcome was achieved in 233 of 284 (82%) timolol-treated migraines, compared to 38 of 271 (14%) placebo-treated migraines (percentage difference = 68 percentage points; 95% CI, 62-74 percentage points; P < .001). The mean pain score at the onset of migraine attacks was 6.01 for those treated with timolol and 5.93 for those treated with placebo. Patients treated with timolol had a reduction in pain of 5.98 points, compared with 0.93 points after using placebo (difference = 5.05; 95% CI, 4.19-5.91). No attacks included in the data required oral rescue medications, and there were no systemic adverse effects from the timolol eyedrops.

WHAT’S NEW

Evidence of benefit as abortive therapy for acute migraine

This randomized controlled trial (RCT) showed evidence to support timolol maleate ophthalmic solution 0.5% vs placebo for treatment of acute migraine by significantly reducing pain when taken at the onset of an acute migraine attack.

CAVEATS

Single-center trial, measuring limited response time

The generalizability of this RCT is limited because it was a single-center trial with a study population from a single region in India. It is unknown whether pain relief, adverse effects, or adherence would differ for the global population. Additionally, only migraines with headache were included in the analysis, limiting non-headache migraine subgroup-directed treatment. Also, this trial evaluated only the response to treatment at 20 minutes, and it is unknown if pain response continued for several hours. Headaches that began more than 20 minutes after the onset of aura were not evaluated.

CHALLENGES TO IMPLEMENTATION

Timolol’s systemic adverse effects require caution

Systemic beta-blocker effects (eg, bradycardia, hypotension, drowsiness, and bronchospasm) from topical timolol have been reported. Caution should be used when prescribing timolol for patients with current cardiovascular and pulmonary conditions. 

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 35-year-old woman with no significant past medical history presents for follow-up of migraine. At the previous visit, she was prescribed sumatriptan for abortive therapy. However, she has been having significant adverse effect intolerance from the oral formulation, and the nasal formulation is cost prohibitive. What can you recommend as an alternative abortive therapy for this patient’s migraine?

Migraine is among the most common causes of disability worldwide, affecting more than 10% of the global population.² The prevalence of migraine is between 2.6% and 21.7% across multiple countries.³ On a scale of 0% to 100%, disability caused by migraine is 43.3%, comparable to the first 2 days after an acute myocardial infarction (42.2%) and severe dementia (43.8%).⁴

Abortive therapy for acute migraine includes nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, ergots, and antiemetics. However, these options are predominantly administered by mouth; non-oral formulations tend to be cost prohibitive and difficult to obtain.

Nausea and vomiting, common components of migraine (that are included in International Classification of Headache Disorders, 3rd edition [ICHD-3] criteria for migraine⁵) present obstacles to effective oral administration if experienced by the patient. In addition, for migraine refractory to first-line treatments, abortive options—including the recently approved calcitonin gene-related peptide (CGRP) receptor antagonists ubrogepant and rimegepant—are also cost prohibitive, potentially costing more than $1000 for 10 tablets (100 mg), depending on insurance coverage.⁶

Two oral beta-blockers, propranolol and timolol, are approved by the US Food and Drug Administration for migraine prophylaxis. Unfortunately, oral beta-blockers are ineffective for abortive treatment.⁷ Ophthalmic timolol is typically used in the treatment of glaucoma, but there have been case reports describing its benefits in acute migraine treatment.^8,9 In addition, ophthalmic timolol is far cheaper than medications such as ubrogepant.¹⁰ A 2014 case series of 7 patients discussed ophthalmic beta-blockers as an effective and possibly cheaper option for acute migraine treatment.⁸ A randomized, crossover, placebo-controlled pilot study of 198 migraine attacks in 10 participants using timolol eyedrops for abortive therapy found timolol was not significantly more effective than placebo.⁹ However, it was an underpowered pilot study, with a lack of masking and an imperfect placebo. The trial discussed here was a controlled, prospective study investigating topical beta-blockers for acute migraine treatment.

STUDY SUMMARY

Crossover study achieved primary endpoint in pain reduction

This randomized, single-center, double-masked, crossover trial compared timolol maleate ophthalmic solution 0.5% with placebo among 43 patients ages 12 or older presenting with a diagnosis of migraine based on ICHD-3 (beta) criteria. Patients were eligible if they had not taken any antimigraine medications for at least 1 month prior to the study and were excluded if they had taken systemic beta-blockers at baseline, or had asthma, bradyarrhythmias, or cardiac dysfunction.

Patients were randomized 1:1 to treatment with timolol maleate 0.5% eyedrops or placebo. At the earliest onset of migraine, patients used 1 drop of timolol maleate 0.5% or placebo in each eye; if they experienced no relief after 10 minutes, they used a second drop or matching placebo. Patients were instructed to score their headache pain on a 10-point scale prior to using the eyedrops and then again 20 minutes after treatment. If a patient had migraine with aura, they were asked to use the eyedrops at the onset of the aura but measure their score at headache onset. If no headaches developed within 20 minutes of the aura, the episode was not included for analysis. All patients were permitted to use their standard oral rescue medication if no relief occurred after 20 minutes of pain onset.

Continue to: The groups were observed...

The groups were observed for 3 months and then followed for a 1-month washout period, during which they received no study medications. The groups were then crossed over to the other treatment and were observed for another 3 months. The primary outcome was a reduction in pain score by 4 or more points, or to 0 on a 10-point pain scale, 20 minutes after treatment. The secondary outcome was nonuse of oral rescue medication.

The primary outcome was achieved in 233 of 284 (82%) timolol-treated migraines, compared to 38 of 271 (14%) placebo-treated migraines.

Forty-three patients were included in a modified intention-to-treat analysis. The primary outcome was achieved in 233 of 284 (82%) timolol-treated migraines, compared to 38 of 271 (14%) placebo-treated migraines (percentage difference = 68 percentage points; 95% CI, 62-74 percentage points; P < .001). The mean pain score at the onset of migraine attacks was 6.01 for those treated with timolol and 5.93 for those treated with placebo. Patients treated with timolol had a reduction in pain of 5.98 points, compared with 0.93 points after using placebo (difference = 5.05; 95% CI, 4.19-5.91). No attacks included in the data required oral rescue medications, and there were no systemic adverse effects from the timolol eyedrops.

WHAT’S NEW

Evidence of benefit as abortive therapy for acute migraine

This randomized controlled trial (RCT) showed evidence to support timolol maleate ophthalmic solution 0.5% vs placebo for treatment of acute migraine by significantly reducing pain when taken at the onset of an acute migraine attack.

CAVEATS

Single-center trial, measuring limited response time

The generalizability of this RCT is limited because it was a single-center trial with a study population from a single region in India. It is unknown whether pain relief, adverse effects, or adherence would differ for the global population. Additionally, only migraines with headache were included in the analysis, limiting non-headache migraine subgroup-directed treatment. Also, this trial evaluated only the response to treatment at 20 minutes, and it is unknown if pain response continued for several hours. Headaches that began more than 20 minutes after the onset of aura were not evaluated.

CHALLENGES TO IMPLEMENTATION

Timolol’s systemic adverse effects require caution

Systemic beta-blocker effects (eg, bradycardia, hypotension, drowsiness, and bronchospasm) from topical timolol have been reported. Caution should be used when prescribing timolol for patients with current cardiovascular and pulmonary conditions. 

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Interventional approaches are being used as a standard of care more and more to provide image-guided techniques to perform minimally invasive procedures. With this being said, what are some indications and best practices used with interventional radiology for the treatment of uterine fibroids?

Dr. Boone:  Interventional radiologists offer minimally invasive non-surgical treatment options for the management of symptomatic uterine fibroids. These approaches include uterine artery embolization or UAE. It may also be called uterine fibroid embolization or UFE.  In this procedure, the uterine arteries are embolized with permanent embolic particles to block blood flow to the fibroids.

The goal of this treatment is to shrink the fibroids. It usually leads to a gradual shrinkage of fibroids and can also be particularly effective for reducing bleeding from fibroids. This procedure has been around for more than 20 years and has a lot of data describing its safety and efficacy.

Another treatment, which is non-invasive, but some interventional radiologists offer, is magnetic resonance-guided focused ultrasound. This might also be called high intensity focused ultrasound or HIFU. In this treatment, MRI is used to direct high intensity ultrasound waves onto the fibroid. This focused application of these high intensity ultrasound waves generates heat and leads to coagulative necrosis of the fibroid.

This procedure is newer than uterine artery embolization, but it has some benefits of avoiding ionizing radiation. Although, it can have longer procedure times. For both procedures, the indications are symptomatic uterine fibroids.

The symptoms we're concerned about include menorrhagia, which can result in anemia. There are also “bulk” symptoms, related to the actual bulk of the fibroids, which can cause bladder or bowel dysfunction. Some patients also have protrusion of their abdomen, dysmenorrhea, and infertility.

The goal is to help reduce those symptoms. The Society for Interventional Radiology has published best practices. For expected outcomes, with the uterine artery embolization, it is 50% to 60% reduction in the size of fibroid of the fibroids themselves, 40% to 50% reduction in the size of the uterus, 88% to 92% of reduction of the bulk symptoms.

Every consultation should discuss the range of treatment options—the medical, surgical, and non-surgical or interventional. I wanted to point out that there is a real need for this. The Society for Interventional Radiology commissioned a poll in 2017 of patients–women  who had been diagnosed with uterine fibroids—and found that 44% of patients noted never hearing of uterine artery embolization. Eleven percent of these patients believed that hysterectomy was their only treatment option. Further, a recent article from NPR noted concerns about disparities in which women of color, particularly Black women, were not offered or made aware of more minimally invasive options during consultations. Very broad patient education about the range of treatment options is important.

In addition, we want to consider other differential diagnoses that patients may have, such as adenomyosis or rare malignancies. Leiomyosarcoma can present with similar symptoms to uterine fibroids or can even coexist with uterine fibroids. In the case of leiomyosarcoma, the treatment pathway may be completely different, and we don't want to undertreat or delay diagnosis. Other considerations that can have bearing on the selection of treatment can be the number and the size of the fibroids.

To help with the decision-making process, these patients need a complete workup. We want to get lab tests. We want to also make sure they have a complete gynecologic evaluation, which includes an ultrasound and an MRI. Particularly, contrast-enhanced MRI has great accuracy for evaluating fibroid location because we’re imaging the entire pelvis. We can see where everything is and map out our target fibroids.

We can also see the enhancement characteristics of the fibroids. Some fibroids are not just supplied by uterine arteries but ovarian arteries, which can affect the efficacy of the treatment and even some of the risks of the treatment.

What is your role and particularly what is the role of the Nurse Practitioner when thinking about diagnosis and treatment and how do you and the nurse practitioner work together?

Dr. Boone: I would say the specific roles for the physicians and nurse practitioners on an interventional radiology team can vary with a lot of different factors. It could depend on the practice setting, such as, whether you're in a busy academic center or in a small private practice. It can depend on the types of cases we're doing. Even some of the local regulations of the institution and state can come into play. The roles tend to be laid out and specified by the supervising physician based on this context.

For example, ideally, all of that work up and planning is happening in that clinic setting before the patient even comes down to the suite for the procedure. In this setting, nurse practitioners can provide a significant role in obtaining the data that we need. They'll perform the history and physical exam, which helps the team learn about the patients. It helps answer relevant questions: What symptoms is the patient having? What are their wishes for the procedure? What are the things they're hoping to avoid or hoping to get from having the procedure done? They review for those relevant labs and imaging, and in order to recognize the information we don’t have.

The next step is developing the assessment and plan which is usually done in conjunction with the interventional radiologist. This is especially important with new patients. Once that assessment and plan are determined, the nurse practitioner can be helpful in explaining the process in depth to the patient and their family or caregivers while they're in the clinic.

Another important role for nurse practitioners in this setting is the consent. I can talk a little bit more about that later, but informed consent is critical. It can be a pretty extensive discussion, especially if we want to talk about this wide range of treatment options. So that is substantial value added by the nurse practitioner.

The other important role is the follow up visits, which may be almost completely independently by a nurse practitioner. They see patients post-procedure, evaluating how they’re doing and what's changed. This is critical because we need to determine: 1. Have we gotten the result that we want? 2. Do we want to give more time to see changes? and;  3. Do we need to do another procedure? We also want to follow these patients and their response to treatment to look out for something concerning that might raise concern for malignancy, such as the fibroid continuing to grow rapidly. Those follow up visits are also a critical role for NPs.

In the inpatient setting, the attending and senior interventional radiology residents may actually determine the roles and tasks the other team members are going to perform to help the IR service run smoothly. And typically, nurse practitioners and also physician assistants will share many of those responsibilities of running that interventional radiology service outside of the procedure room.

There are also cases where nurse practitioners and physician assistants can have a dedicated role in performing certain procedures. Personally, I've seen physician assistants in these cases, where they were our dedicated bone marrow biopsy providers. Throughout the day, they would do all the bone marrow biopsy cases. Another example I saw was placement of vascular access catheters, whether for ports or dialysis. NPs see many patients throughout the day and perform these procedures. This is helpful because these are very popular procedures and are needed. While those are being done, it frees up time for the other members of the team to do other, more time-consuming, procedures as well.

In all cases, we work closely together. We're sharing this responsibility of patient care. We communicate frequently and it's a valuable team dynamic. NPs are fantastic team members

Dr. Boone, you talked about the treatments and how you work together with NPs. Can you touch on the interventional procedures and the value or benefit over conservative treatments and drugs, particularly, where you receive support or recommendations from nurse practitioners at this stage?

Dr. Boone: Regarding more conservative treatment,  there’s expectant management where the patients may not want to undergo an intervention at that time. You’re following the patient and watching for possible worsening of symptoms that may lead to a change in management.

There’s also medical management, which generally gets broken down into hormonal or non-hormonal medications. Among these, there's a lot of different drugs that are available. Among the more frequently used hormonal therapies would be gonadotropin-releasing hormone agonists.

The non-hormonal therapies such as, NSAIDs, or procoagulation medications, like tranexamic acid, are more targeted at symptom control. Particularly, these target the abnormal uterine bleeding and the pain.

For these therapies, the limitations can be side-effect profiles. Sometimes these side effects are just not acceptable to patients. Hormonal therapies like the gonadotropin-releasing hormone agonists create this hypoestrogenic state. Patients may not like having the menopause-like symptoms.

Additionally, medications are more short-term in their benefit. For example, with the cessation of gonadotropin-releasing hormone agonists, the fibroids actually can show rapid rebound growth. Some of the non-surgical interventions can provide longer term benefit, even if they may require re-intervention more frequently compared to surgical interventions.

For interventional radiology, we primarily focus on the procedures. We don't typically manage the medical therapy. These treatment approaches are cultivated more by gynecology or other clinicians.

When it comes to interventional radiology treatment for uterine fibroids in your day-to-day practices, which you've talked a lot about today, what has been your experience in working with Nurse Practitioners overall and where do they, should they or could they potentially add even more value?

Dr. Boone: Nurse practitioners play an integral role on the team and, I think, they provide a lot of value. They have an important role in teaching settings, were they provide continuity of care. They can also greatly impact with teaching of trainees.

In teaching settings, there's a substantial turnover of trainees because -- and this includes residents, medical students, in some cases fellows -- they're  rotating between different hospitals every few weeks. Even at the end of the year, the most senior residents, the most experience trainees, leave to go to new jobs. Nurse practitioners on the IR team are a critical source of continuity and consistency for patients and for the rest of the team because they spend the most time on the service and they know the team members well. They also know how to get things done efficiently and really know the system.

They've also honed the skills that trainees, particularly junior residents, are learning. In my experience, I first learned to place and remove tunneled catheters and bone marrow biopsies by spending the day with a physician assistant and a nurse practitioner. Both from the educational standpoint and also consistent, efficient care standpoint, having NPs and PAs on our team is hugely valuable.

Emphasizing that role in teaching is highly valuable. I would encourage nurse practitioners on an IR team with trainees to take ownership of teaching a particular skill or a certain topic, because they're going to bring a different perspective and that's extremely valuable.

Another arena where there's a lot of value, is  in the informed consent and patient education portion of patient care. Interventional radiology is not the most familiar medical field for a lot of people. Interventional radiologists also perform a wide array of procedures and they can be very different. Even treatments for the same problem, uterine artery embolization and MRI-guided focused ultrasound, are very different procedures in terms of how they're actually performed.

For example, if you mentioned surgery to most people, there is some idea of what that entails and who performs it. But if you say embolization to most people, they may not entirely understand all those components. For a patient to sufficiently be informed and able to consent, they do need to understand not only their disease and the treatment being offered, but also the risks, the benefits, and the alternatives. They need to understand what to expect from the procedure.

Doing this well can take a substantial amount of time, but it is important. From a physician standpoint, that entails balancing. Along with performing the procedures and reviewing patient imaging as well as other clinical duties this is very  challenging. Nurse practitioners can really leverage their expertise in patient communication and education to fill in those knowledge gaps and best serve the patient while also helping the IR service. These are just two of many areas in which NPs can be highly valuable to an IR practice.

Interventional approaches are being used as a standard of care more and more to provide image-guided techniques to perform minimally invasive procedures. With this being said, what are some indications and best practices used with interventional radiology for the treatment of uterine fibroids?

Dr. Boone:  Interventional radiologists offer minimally invasive non-surgical treatment options for the management of symptomatic uterine fibroids. These approaches include uterine artery embolization or UAE. It may also be called uterine fibroid embolization or UFE.  In this procedure, the uterine arteries are embolized with permanent embolic particles to block blood flow to the fibroids.

The goal of this treatment is to shrink the fibroids. It usually leads to a gradual shrinkage of fibroids and can also be particularly effective for reducing bleeding from fibroids. This procedure has been around for more than 20 years and has a lot of data describing its safety and efficacy.

Another treatment, which is non-invasive, but some interventional radiologists offer, is magnetic resonance-guided focused ultrasound. This might also be called high intensity focused ultrasound or HIFU. In this treatment, MRI is used to direct high intensity ultrasound waves onto the fibroid. This focused application of these high intensity ultrasound waves generates heat and leads to coagulative necrosis of the fibroid.

This procedure is newer than uterine artery embolization, but it has some benefits of avoiding ionizing radiation. Although, it can have longer procedure times. For both procedures, the indications are symptomatic uterine fibroids.

The symptoms we're concerned about include menorrhagia, which can result in anemia. There are also “bulk” symptoms, related to the actual bulk of the fibroids, which can cause bladder or bowel dysfunction. Some patients also have protrusion of their abdomen, dysmenorrhea, and infertility.

The goal is to help reduce those symptoms. The Society for Interventional Radiology has published best practices. For expected outcomes, with the uterine artery embolization, it is 50% to 60% reduction in the size of fibroid of the fibroids themselves, 40% to 50% reduction in the size of the uterus, 88% to 92% of reduction of the bulk symptoms.

Every consultation should discuss the range of treatment options—the medical, surgical, and non-surgical or interventional. I wanted to point out that there is a real need for this. The Society for Interventional Radiology commissioned a poll in 2017 of patients–women  who had been diagnosed with uterine fibroids—and found that 44% of patients noted never hearing of uterine artery embolization. Eleven percent of these patients believed that hysterectomy was their only treatment option. Further, a recent article from NPR noted concerns about disparities in which women of color, particularly Black women, were not offered or made aware of more minimally invasive options during consultations. Very broad patient education about the range of treatment options is important.

In addition, we want to consider other differential diagnoses that patients may have, such as adenomyosis or rare malignancies. Leiomyosarcoma can present with similar symptoms to uterine fibroids or can even coexist with uterine fibroids. In the case of leiomyosarcoma, the treatment pathway may be completely different, and we don't want to undertreat or delay diagnosis. Other considerations that can have bearing on the selection of treatment can be the number and the size of the fibroids.

To help with the decision-making process, these patients need a complete workup. We want to get lab tests. We want to also make sure they have a complete gynecologic evaluation, which includes an ultrasound and an MRI. Particularly, contrast-enhanced MRI has great accuracy for evaluating fibroid location because we’re imaging the entire pelvis. We can see where everything is and map out our target fibroids.

We can also see the enhancement characteristics of the fibroids. Some fibroids are not just supplied by uterine arteries but ovarian arteries, which can affect the efficacy of the treatment and even some of the risks of the treatment.

What is your role and particularly what is the role of the Nurse Practitioner when thinking about diagnosis and treatment and how do you and the nurse practitioner work together?

Dr. Boone: I would say the specific roles for the physicians and nurse practitioners on an interventional radiology team can vary with a lot of different factors. It could depend on the practice setting, such as, whether you're in a busy academic center or in a small private practice. It can depend on the types of cases we're doing. Even some of the local regulations of the institution and state can come into play. The roles tend to be laid out and specified by the supervising physician based on this context.

For example, ideally, all of that work up and planning is happening in that clinic setting before the patient even comes down to the suite for the procedure. In this setting, nurse practitioners can provide a significant role in obtaining the data that we need. They'll perform the history and physical exam, which helps the team learn about the patients. It helps answer relevant questions: What symptoms is the patient having? What are their wishes for the procedure? What are the things they're hoping to avoid or hoping to get from having the procedure done? They review for those relevant labs and imaging, and in order to recognize the information we don’t have.

The next step is developing the assessment and plan which is usually done in conjunction with the interventional radiologist. This is especially important with new patients. Once that assessment and plan are determined, the nurse practitioner can be helpful in explaining the process in depth to the patient and their family or caregivers while they're in the clinic.

Another important role for nurse practitioners in this setting is the consent. I can talk a little bit more about that later, but informed consent is critical. It can be a pretty extensive discussion, especially if we want to talk about this wide range of treatment options. So that is substantial value added by the nurse practitioner.

The other important role is the follow up visits, which may be almost completely independently by a nurse practitioner. They see patients post-procedure, evaluating how they’re doing and what's changed. This is critical because we need to determine: 1. Have we gotten the result that we want? 2. Do we want to give more time to see changes? and;  3. Do we need to do another procedure? We also want to follow these patients and their response to treatment to look out for something concerning that might raise concern for malignancy, such as the fibroid continuing to grow rapidly. Those follow up visits are also a critical role for NPs.

In the inpatient setting, the attending and senior interventional radiology residents may actually determine the roles and tasks the other team members are going to perform to help the IR service run smoothly. And typically, nurse practitioners and also physician assistants will share many of those responsibilities of running that interventional radiology service outside of the procedure room.

There are also cases where nurse practitioners and physician assistants can have a dedicated role in performing certain procedures. Personally, I've seen physician assistants in these cases, where they were our dedicated bone marrow biopsy providers. Throughout the day, they would do all the bone marrow biopsy cases. Another example I saw was placement of vascular access catheters, whether for ports or dialysis. NPs see many patients throughout the day and perform these procedures. This is helpful because these are very popular procedures and are needed. While those are being done, it frees up time for the other members of the team to do other, more time-consuming, procedures as well.

In all cases, we work closely together. We're sharing this responsibility of patient care. We communicate frequently and it's a valuable team dynamic. NPs are fantastic team members

Dr. Boone, you talked about the treatments and how you work together with NPs. Can you touch on the interventional procedures and the value or benefit over conservative treatments and drugs, particularly, where you receive support or recommendations from nurse practitioners at this stage?

Dr. Boone: Regarding more conservative treatment,  there’s expectant management where the patients may not want to undergo an intervention at that time. You’re following the patient and watching for possible worsening of symptoms that may lead to a change in management.

There’s also medical management, which generally gets broken down into hormonal or non-hormonal medications. Among these, there's a lot of different drugs that are available. Among the more frequently used hormonal therapies would be gonadotropin-releasing hormone agonists.

The non-hormonal therapies such as, NSAIDs, or procoagulation medications, like tranexamic acid, are more targeted at symptom control. Particularly, these target the abnormal uterine bleeding and the pain.

For these therapies, the limitations can be side-effect profiles. Sometimes these side effects are just not acceptable to patients. Hormonal therapies like the gonadotropin-releasing hormone agonists create this hypoestrogenic state. Patients may not like having the menopause-like symptoms.

Additionally, medications are more short-term in their benefit. For example, with the cessation of gonadotropin-releasing hormone agonists, the fibroids actually can show rapid rebound growth. Some of the non-surgical interventions can provide longer term benefit, even if they may require re-intervention more frequently compared to surgical interventions.

For interventional radiology, we primarily focus on the procedures. We don't typically manage the medical therapy. These treatment approaches are cultivated more by gynecology or other clinicians.

When it comes to interventional radiology treatment for uterine fibroids in your day-to-day practices, which you've talked a lot about today, what has been your experience in working with Nurse Practitioners overall and where do they, should they or could they potentially add even more value?

Dr. Boone: Nurse practitioners play an integral role on the team and, I think, they provide a lot of value. They have an important role in teaching settings, were they provide continuity of care. They can also greatly impact with teaching of trainees.

In teaching settings, there's a substantial turnover of trainees because -- and this includes residents, medical students, in some cases fellows -- they're  rotating between different hospitals every few weeks. Even at the end of the year, the most senior residents, the most experience trainees, leave to go to new jobs. Nurse practitioners on the IR team are a critical source of continuity and consistency for patients and for the rest of the team because they spend the most time on the service and they know the team members well. They also know how to get things done efficiently and really know the system.

They've also honed the skills that trainees, particularly junior residents, are learning. In my experience, I first learned to place and remove tunneled catheters and bone marrow biopsies by spending the day with a physician assistant and a nurse practitioner. Both from the educational standpoint and also consistent, efficient care standpoint, having NPs and PAs on our team is hugely valuable.

Emphasizing that role in teaching is highly valuable. I would encourage nurse practitioners on an IR team with trainees to take ownership of teaching a particular skill or a certain topic, because they're going to bring a different perspective and that's extremely valuable.

Another arena where there's a lot of value, is  in the informed consent and patient education portion of patient care. Interventional radiology is not the most familiar medical field for a lot of people. Interventional radiologists also perform a wide array of procedures and they can be very different. Even treatments for the same problem, uterine artery embolization and MRI-guided focused ultrasound, are very different procedures in terms of how they're actually performed.

For example, if you mentioned surgery to most people, there is some idea of what that entails and who performs it. But if you say embolization to most people, they may not entirely understand all those components. For a patient to sufficiently be informed and able to consent, they do need to understand not only their disease and the treatment being offered, but also the risks, the benefits, and the alternatives. They need to understand what to expect from the procedure.

Doing this well can take a substantial amount of time, but it is important. From a physician standpoint, that entails balancing. Along with performing the procedures and reviewing patient imaging as well as other clinical duties this is very  challenging. Nurse practitioners can really leverage their expertise in patient communication and education to fill in those knowledge gaps and best serve the patient while also helping the IR service. These are just two of many areas in which NPs can be highly valuable to an IR practice.

Interventional approaches are being used as a standard of care more and more to provide image-guided techniques to perform minimally invasive procedures. With this being said, what are some indications and best practices used with interventional radiology for the treatment of uterine fibroids?

Dr. Boone:  Interventional radiologists offer minimally invasive non-surgical treatment options for the management of symptomatic uterine fibroids. These approaches include uterine artery embolization or UAE. It may also be called uterine fibroid embolization or UFE.  In this procedure, the uterine arteries are embolized with permanent embolic particles to block blood flow to the fibroids.

The goal of this treatment is to shrink the fibroids. It usually leads to a gradual shrinkage of fibroids and can also be particularly effective for reducing bleeding from fibroids. This procedure has been around for more than 20 years and has a lot of data describing its safety and efficacy.

Another treatment, which is non-invasive, but some interventional radiologists offer, is magnetic resonance-guided focused ultrasound. This might also be called high intensity focused ultrasound or HIFU. In this treatment, MRI is used to direct high intensity ultrasound waves onto the fibroid. This focused application of these high intensity ultrasound waves generates heat and leads to coagulative necrosis of the fibroid.

This procedure is newer than uterine artery embolization, but it has some benefits of avoiding ionizing radiation. Although, it can have longer procedure times. For both procedures, the indications are symptomatic uterine fibroids.

The symptoms we're concerned about include menorrhagia, which can result in anemia. There are also “bulk” symptoms, related to the actual bulk of the fibroids, which can cause bladder or bowel dysfunction. Some patients also have protrusion of their abdomen, dysmenorrhea, and infertility.

The goal is to help reduce those symptoms. The Society for Interventional Radiology has published best practices. For expected outcomes, with the uterine artery embolization, it is 50% to 60% reduction in the size of fibroid of the fibroids themselves, 40% to 50% reduction in the size of the uterus, 88% to 92% of reduction of the bulk symptoms.

Every consultation should discuss the range of treatment options—the medical, surgical, and non-surgical or interventional. I wanted to point out that there is a real need for this. The Society for Interventional Radiology commissioned a poll in 2017 of patients–women  who had been diagnosed with uterine fibroids—and found that 44% of patients noted never hearing of uterine artery embolization. Eleven percent of these patients believed that hysterectomy was their only treatment option. Further, a recent article from NPR noted concerns about disparities in which women of color, particularly Black women, were not offered or made aware of more minimally invasive options during consultations. Very broad patient education about the range of treatment options is important.

In addition, we want to consider other differential diagnoses that patients may have, such as adenomyosis or rare malignancies. Leiomyosarcoma can present with similar symptoms to uterine fibroids or can even coexist with uterine fibroids. In the case of leiomyosarcoma, the treatment pathway may be completely different, and we don't want to undertreat or delay diagnosis. Other considerations that can have bearing on the selection of treatment can be the number and the size of the fibroids.

To help with the decision-making process, these patients need a complete workup. We want to get lab tests. We want to also make sure they have a complete gynecologic evaluation, which includes an ultrasound and an MRI. Particularly, contrast-enhanced MRI has great accuracy for evaluating fibroid location because we’re imaging the entire pelvis. We can see where everything is and map out our target fibroids.

We can also see the enhancement characteristics of the fibroids. Some fibroids are not just supplied by uterine arteries but ovarian arteries, which can affect the efficacy of the treatment and even some of the risks of the treatment.

What is your role and particularly what is the role of the Nurse Practitioner when thinking about diagnosis and treatment and how do you and the nurse practitioner work together?

Dr. Boone: I would say the specific roles for the physicians and nurse practitioners on an interventional radiology team can vary with a lot of different factors. It could depend on the practice setting, such as, whether you're in a busy academic center or in a small private practice. It can depend on the types of cases we're doing. Even some of the local regulations of the institution and state can come into play. The roles tend to be laid out and specified by the supervising physician based on this context.

For example, ideally, all of that work up and planning is happening in that clinic setting before the patient even comes down to the suite for the procedure. In this setting, nurse practitioners can provide a significant role in obtaining the data that we need. They'll perform the history and physical exam, which helps the team learn about the patients. It helps answer relevant questions: What symptoms is the patient having? What are their wishes for the procedure? What are the things they're hoping to avoid or hoping to get from having the procedure done? They review for those relevant labs and imaging, and in order to recognize the information we don’t have.

The next step is developing the assessment and plan which is usually done in conjunction with the interventional radiologist. This is especially important with new patients. Once that assessment and plan are determined, the nurse practitioner can be helpful in explaining the process in depth to the patient and their family or caregivers while they're in the clinic.

Another important role for nurse practitioners in this setting is the consent. I can talk a little bit more about that later, but informed consent is critical. It can be a pretty extensive discussion, especially if we want to talk about this wide range of treatment options. So that is substantial value added by the nurse practitioner.

The other important role is the follow up visits, which may be almost completely independently by a nurse practitioner. They see patients post-procedure, evaluating how they’re doing and what's changed. This is critical because we need to determine: 1. Have we gotten the result that we want? 2. Do we want to give more time to see changes? and;  3. Do we need to do another procedure? We also want to follow these patients and their response to treatment to look out for something concerning that might raise concern for malignancy, such as the fibroid continuing to grow rapidly. Those follow up visits are also a critical role for NPs.

In the inpatient setting, the attending and senior interventional radiology residents may actually determine the roles and tasks the other team members are going to perform to help the IR service run smoothly. And typically, nurse practitioners and also physician assistants will share many of those responsibilities of running that interventional radiology service outside of the procedure room.

There are also cases where nurse practitioners and physician assistants can have a dedicated role in performing certain procedures. Personally, I've seen physician assistants in these cases, where they were our dedicated bone marrow biopsy providers. Throughout the day, they would do all the bone marrow biopsy cases. Another example I saw was placement of vascular access catheters, whether for ports or dialysis. NPs see many patients throughout the day and perform these procedures. This is helpful because these are very popular procedures and are needed. While those are being done, it frees up time for the other members of the team to do other, more time-consuming, procedures as well.

In all cases, we work closely together. We're sharing this responsibility of patient care. We communicate frequently and it's a valuable team dynamic. NPs are fantastic team members

Dr. Boone, you talked about the treatments and how you work together with NPs. Can you touch on the interventional procedures and the value or benefit over conservative treatments and drugs, particularly, where you receive support or recommendations from nurse practitioners at this stage?

Dr. Boone: Regarding more conservative treatment,  there’s expectant management where the patients may not want to undergo an intervention at that time. You’re following the patient and watching for possible worsening of symptoms that may lead to a change in management.

There’s also medical management, which generally gets broken down into hormonal or non-hormonal medications. Among these, there's a lot of different drugs that are available. Among the more frequently used hormonal therapies would be gonadotropin-releasing hormone agonists.

The non-hormonal therapies such as, NSAIDs, or procoagulation medications, like tranexamic acid, are more targeted at symptom control. Particularly, these target the abnormal uterine bleeding and the pain.

For these therapies, the limitations can be side-effect profiles. Sometimes these side effects are just not acceptable to patients. Hormonal therapies like the gonadotropin-releasing hormone agonists create this hypoestrogenic state. Patients may not like having the menopause-like symptoms.

Additionally, medications are more short-term in their benefit. For example, with the cessation of gonadotropin-releasing hormone agonists, the fibroids actually can show rapid rebound growth. Some of the non-surgical interventions can provide longer term benefit, even if they may require re-intervention more frequently compared to surgical interventions.

For interventional radiology, we primarily focus on the procedures. We don't typically manage the medical therapy. These treatment approaches are cultivated more by gynecology or other clinicians.

When it comes to interventional radiology treatment for uterine fibroids in your day-to-day practices, which you've talked a lot about today, what has been your experience in working with Nurse Practitioners overall and where do they, should they or could they potentially add even more value?

Dr. Boone: Nurse practitioners play an integral role on the team and, I think, they provide a lot of value. They have an important role in teaching settings, were they provide continuity of care. They can also greatly impact with teaching of trainees.

In teaching settings, there's a substantial turnover of trainees because -- and this includes residents, medical students, in some cases fellows -- they're  rotating between different hospitals every few weeks. Even at the end of the year, the most senior residents, the most experience trainees, leave to go to new jobs. Nurse practitioners on the IR team are a critical source of continuity and consistency for patients and for the rest of the team because they spend the most time on the service and they know the team members well. They also know how to get things done efficiently and really know the system.

They've also honed the skills that trainees, particularly junior residents, are learning. In my experience, I first learned to place and remove tunneled catheters and bone marrow biopsies by spending the day with a physician assistant and a nurse practitioner. Both from the educational standpoint and also consistent, efficient care standpoint, having NPs and PAs on our team is hugely valuable.

Emphasizing that role in teaching is highly valuable. I would encourage nurse practitioners on an IR team with trainees to take ownership of teaching a particular skill or a certain topic, because they're going to bring a different perspective and that's extremely valuable.

Another arena where there's a lot of value, is  in the informed consent and patient education portion of patient care. Interventional radiology is not the most familiar medical field for a lot of people. Interventional radiologists also perform a wide array of procedures and they can be very different. Even treatments for the same problem, uterine artery embolization and MRI-guided focused ultrasound, are very different procedures in terms of how they're actually performed.

For example, if you mentioned surgery to most people, there is some idea of what that entails and who performs it. But if you say embolization to most people, they may not entirely understand all those components. For a patient to sufficiently be informed and able to consent, they do need to understand not only their disease and the treatment being offered, but also the risks, the benefits, and the alternatives. They need to understand what to expect from the procedure.

Doing this well can take a substantial amount of time, but it is important. From a physician standpoint, that entails balancing. Along with performing the procedures and reviewing patient imaging as well as other clinical duties this is very  challenging. Nurse practitioners can really leverage their expertise in patient communication and education to fill in those knowledge gaps and best serve the patient while also helping the IR service. These are just two of many areas in which NPs can be highly valuable to an IR practice.

Tampons may be harder to find because of supply chain challenges and inflation hikes that are causing higher prices.

Social media users have posted about bare shelves and higher costs for months, marking the latest products to face stress under global supply chain concerns after baby formula, cars, and appliances.

Other menstrual products have increased in price as well because of inflation, according to Bloomberg News. The average price for a package of menstrual pads has increased about 8% this year, and the price of a box of tampons has increased about 10%.

Andre Schulten, the chief financial officer for Procter & Gamble, which makes and sells 4.5 billion boxes of Tampax each year, said on a recent earnings call that it has been “costly and highly volatile” to acquire the raw materials needed for production.

Raw materials such as cotton, rayon, and plastic, for instance, have been used to produce personal protective gear during the pandemic, which has led to shortages. The cost of transportation for consumer goods has also nearly tripled, and pandemic policies at ports have led to shipping delays.

Edgewell Personal Care, which makes the brands Playtex and o.b., has had a severe staff shortage at its Delaware facility where tampons are made, according to Time. The FDA has classified tampons as class II medical devices, which require certain quality-control regulations and qualified workers on the assembly line, the news outlet reported.

Representatives for CVS and Walgreens confirmed that they’ve had shortages in recent weeks, according to The Washington Post. Procter & Gamble said it is working with retail partners to make feminine care products more available.

“We understand it is frustrating for consumers when they can’t find what they need,” the company told the newspaper. “We can assure you this is a temporary situation.”

Kimberly-Clark, which makes U by Kotex tampons, told the Post that it “has not experienced a product or supply shortage” in the United States, saying it is “working closely with our retail partners to keep shelves stocked.”

But the shortage may grow worse as the year goes on and the peak season for shipping approaches, the newspaper reported.

“Capacity is only going to get tighter as we move toward the end of the year,” Vaughn Moore, chief executive of AIT Worldwide Logistics, told the Post.

While the situation is being straightened out, gynecologists have recommended against extending supply at home by wearing tampons for longer stretches of time, according to The New York Times. Toxic shock syndrome is a rare but potentially fatal condition that can occur when tampons are worn for more than 8 hours.

There are other options, such as reusable menstrual pads, period underwear, and menstrual cups and discs, the Times reported. But some of these may be less appealing to use, or they may cost too much.

A version of this article first appeared on WebMD.com.

Tampons may be harder to find because of supply chain challenges and inflation hikes that are causing higher prices.

Social media users have posted about bare shelves and higher costs for months, marking the latest products to face stress under global supply chain concerns after baby formula, cars, and appliances.

Other menstrual products have increased in price as well because of inflation, according to Bloomberg News. The average price for a package of menstrual pads has increased about 8% this year, and the price of a box of tampons has increased about 10%.

Andre Schulten, the chief financial officer for Procter & Gamble, which makes and sells 4.5 billion boxes of Tampax each year, said on a recent earnings call that it has been “costly and highly volatile” to acquire the raw materials needed for production.

Raw materials such as cotton, rayon, and plastic, for instance, have been used to produce personal protective gear during the pandemic, which has led to shortages. The cost of transportation for consumer goods has also nearly tripled, and pandemic policies at ports have led to shipping delays.

Edgewell Personal Care, which makes the brands Playtex and o.b., has had a severe staff shortage at its Delaware facility where tampons are made, according to Time. The FDA has classified tampons as class II medical devices, which require certain quality-control regulations and qualified workers on the assembly line, the news outlet reported.

Representatives for CVS and Walgreens confirmed that they’ve had shortages in recent weeks, according to The Washington Post. Procter & Gamble said it is working with retail partners to make feminine care products more available.

“We understand it is frustrating for consumers when they can’t find what they need,” the company told the newspaper. “We can assure you this is a temporary situation.”

Kimberly-Clark, which makes U by Kotex tampons, told the Post that it “has not experienced a product or supply shortage” in the United States, saying it is “working closely with our retail partners to keep shelves stocked.”

But the shortage may grow worse as the year goes on and the peak season for shipping approaches, the newspaper reported.

“Capacity is only going to get tighter as we move toward the end of the year,” Vaughn Moore, chief executive of AIT Worldwide Logistics, told the Post.

While the situation is being straightened out, gynecologists have recommended against extending supply at home by wearing tampons for longer stretches of time, according to The New York Times. Toxic shock syndrome is a rare but potentially fatal condition that can occur when tampons are worn for more than 8 hours.

There are other options, such as reusable menstrual pads, period underwear, and menstrual cups and discs, the Times reported. But some of these may be less appealing to use, or they may cost too much.

A version of this article first appeared on WebMD.com.

Tampons may be harder to find because of supply chain challenges and inflation hikes that are causing higher prices.

Social media users have posted about bare shelves and higher costs for months, marking the latest products to face stress under global supply chain concerns after baby formula, cars, and appliances.

Other menstrual products have increased in price as well because of inflation, according to Bloomberg News. The average price for a package of menstrual pads has increased about 8% this year, and the price of a box of tampons has increased about 10%.

Andre Schulten, the chief financial officer for Procter & Gamble, which makes and sells 4.5 billion boxes of Tampax each year, said on a recent earnings call that it has been “costly and highly volatile” to acquire the raw materials needed for production.

Raw materials such as cotton, rayon, and plastic, for instance, have been used to produce personal protective gear during the pandemic, which has led to shortages. The cost of transportation for consumer goods has also nearly tripled, and pandemic policies at ports have led to shipping delays.

Edgewell Personal Care, which makes the brands Playtex and o.b., has had a severe staff shortage at its Delaware facility where tampons are made, according to Time. The FDA has classified tampons as class II medical devices, which require certain quality-control regulations and qualified workers on the assembly line, the news outlet reported.

Representatives for CVS and Walgreens confirmed that they’ve had shortages in recent weeks, according to The Washington Post. Procter & Gamble said it is working with retail partners to make feminine care products more available.

“We understand it is frustrating for consumers when they can’t find what they need,” the company told the newspaper. “We can assure you this is a temporary situation.”

Kimberly-Clark, which makes U by Kotex tampons, told the Post that it “has not experienced a product or supply shortage” in the United States, saying it is “working closely with our retail partners to keep shelves stocked.”

But the shortage may grow worse as the year goes on and the peak season for shipping approaches, the newspaper reported.

“Capacity is only going to get tighter as we move toward the end of the year,” Vaughn Moore, chief executive of AIT Worldwide Logistics, told the Post.

While the situation is being straightened out, gynecologists have recommended against extending supply at home by wearing tampons for longer stretches of time, according to The New York Times. Toxic shock syndrome is a rare but potentially fatal condition that can occur when tampons are worn for more than 8 hours.

There are other options, such as reusable menstrual pads, period underwear, and menstrual cups and discs, the Times reported. But some of these may be less appealing to use, or they may cost too much.

A version of this article first appeared on WebMD.com.

Adding psychotherapy to pharmacologic treatment does not appear to improve treatment outcomes for patients with major depression, new research suggests.

Results of a cross-sectional, naturalistic, multicenter European study showed there were no significant differences in response rates between patients with major depressive disorder (MDD) who received combination treatment with psychotherapy and antidepressant medication in comparison with those who received antidepressant monotherapy, even when comparing different types of psychotherapy.

This “might emphasize the fundamental role of the underlying complex biological interrelationships in MDD and its treatment,” said study investigator Lucie Bartova, MD, PhD, Clinical Division of General Psychiatry, Medical University of Vienna.

However, she noted that patients who received psychotherapy in combination with antidepressants also had “beneficial sociodemographic and clinical characteristics,” which might reflect poorer access to “psychotherapeutic techniques for patients who are more severely ill and have less socioeconomic privilege.”

The resulting selection bias may cause patients with more severe illness to “fall by the wayside,” Dr. Bartova said.

Lead researcher Siegfried Kasper, MD, also from the Medical University of Vienna, agreed, saying in a press release that, by implication, “additional psychotherapy tends to be given to more highly educated and healthier patients, which may reflect the greater availability of psychotherapy to more socially and economically advantaged patients.”

The findings, some of which were previously published in the Journal of Psychiatry Research, were presented at the virtual European Psychiatric Association 2022 Congress.
 

Inconsistent guidelines

During her presentation, Dr. Bartova said that while “numerous effective antidepressant strategies are available for the treatment of MDD, many patients do not achieve a satisfactory treatment response,” which often leads to further management refinement and the use of off-label treatments.

She continued, saying that the “most obvious” approach in these situations is to try the available treatment options in a “systematic and individualized” manner, ideally by following recommended treatment algorithms.

Meta-analyses have suggested that standardized psychotherapy with fixed, regular sessions that follows an established rationale and is based on a defined school of thought is effective in MDD, “with at least moderate effects.”

Among the psychotherapy approaches, cognitive-behavioral therapy (CBT) is the “best and most investigated,” Dr. Bartova said, but international clinical practice guidelines “lack consistency” regarding recommendations for psychotherapy.

To examine the use and impact of psychotherapy for MDD patients, the researchers studied 1,410 adult inpatients and outpatients from 10 centers in eight countries who were surveyed between 2011 and 2016 by the European Group for the Study of Resistant Depression.

Participants were assessed via the Mini–International Neuropsychiatric Interview, the Montgomery-Åsberg Depression Rating Scale, and the Hamilton Depression Rating Scale.

Results showed that among 1,279 MDD patients who were included in the final analysis, 880 (68.8%) received only antidepressants, while 399 (31.2%) received some form of structured psychotherapy as part of their treatment.

These patients included 22.8% who received CBT, 3.4% who underwent psychoanalytic psychotherapy, and 1.3% who received systemic psychotherapy. The additional psychotherapy was not specified for 3.8%.

Dr. Bartova explained that the use of psychotherapy in combination pharmacologic treatment was significantly associated with younger age, higher educational attainment, and ongoing employment in comparison with antidepressant use alone (P < .001 for all).

In addition, combination therapy was associated with an earlier average age of MDD onset, lower severity of current depressive symptoms, a lower risk of suicidality, higher rates of additional melancholic features in the patients’ symptomatology, and higher rates of comorbid asthma and migraine (P < .001 for all).

There was also a significant association between the use of psychotherapy plus pharmacologic treatment and lower average daily doses of first-line antidepressant medication (P < .001), as well as more frequent administration of agomelatine (P < .001) and a trend toward greater use of vortioxetine (P = .006).

In contrast, among patients who received antidepressants alone, there was a trend toward higher rates of additional psychotic features (P = .054), and the patients were more likely to have received selective serotonin reuptake inhibitors as their first-line antidepressant medication (P < .001).

The researchers found there was no significant difference in rates of response, nonresponse, and treatment-resistant depression (TRD) between patients who received combination psychotherapy and pharmacotherapy and those who received antidepressants alone (P = .369).

Dr. Bartova showed that 25.8% of MDD patients who received combination therapy were classified as responders, compared with 23.5% of those given only antidepressants. Nonresponse was identified in 35.6% and 33.8% of patients, respectively, while 38.6% versus 42.7% had TRD.

Dr. Bartova and colleagues performed an additional analysis to determine whether there was any difference in response depending on the type of psychotherapy.

They divided patients who received combination therapy into those who had received CBT and those who had been given another form of psychotherapy.

Again, there were no significant differences in response, nonresponse, and TRD (P = .256). The response rate was 27.1% among patients given combination CBT, versus 22.4% among those who received another psychotherapy.

“Despite clinical guidelines and studies which advocate for psychotherapy and combining psychotherapy with antidepressants, this study shows that in real life, no added value can be demonstrated for psychotherapy in those already treated with antidepressants for severe depression,” Livia De Picker, MD, PhD, Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Belgium, said in the press release.

“This doesn’t necessarily mean that psychotherapy is not useful, but it is a clear sign that the way we are currently managing these depressed patients with psychotherapy is not effective and needs critical evaluation,” added Dr. De Picker, who was not involved in the research.

However, Michael E. Thase, MD, professor of psychiatry, University of Pennsylvania, Philadelphia, told this news organization that the current study “is a secondary analysis of a naturalistic study.”

A version of this article first appeared on Medscape.com.

Adding psychotherapy to pharmacologic treatment does not appear to improve treatment outcomes for patients with major depression, new research suggests.

Results of a cross-sectional, naturalistic, multicenter European study showed there were no significant differences in response rates between patients with major depressive disorder (MDD) who received combination treatment with psychotherapy and antidepressant medication in comparison with those who received antidepressant monotherapy, even when comparing different types of psychotherapy.

This “might emphasize the fundamental role of the underlying complex biological interrelationships in MDD and its treatment,” said study investigator Lucie Bartova, MD, PhD, Clinical Division of General Psychiatry, Medical University of Vienna.

However, she noted that patients who received psychotherapy in combination with antidepressants also had “beneficial sociodemographic and clinical characteristics,” which might reflect poorer access to “psychotherapeutic techniques for patients who are more severely ill and have less socioeconomic privilege.”

The resulting selection bias may cause patients with more severe illness to “fall by the wayside,” Dr. Bartova said.

Lead researcher Siegfried Kasper, MD, also from the Medical University of Vienna, agreed, saying in a press release that, by implication, “additional psychotherapy tends to be given to more highly educated and healthier patients, which may reflect the greater availability of psychotherapy to more socially and economically advantaged patients.”

The findings, some of which were previously published in the Journal of Psychiatry Research, were presented at the virtual European Psychiatric Association 2022 Congress.
 

Inconsistent guidelines

During her presentation, Dr. Bartova said that while “numerous effective antidepressant strategies are available for the treatment of MDD, many patients do not achieve a satisfactory treatment response,” which often leads to further management refinement and the use of off-label treatments.

She continued, saying that the “most obvious” approach in these situations is to try the available treatment options in a “systematic and individualized” manner, ideally by following recommended treatment algorithms.

Meta-analyses have suggested that standardized psychotherapy with fixed, regular sessions that follows an established rationale and is based on a defined school of thought is effective in MDD, “with at least moderate effects.”

Among the psychotherapy approaches, cognitive-behavioral therapy (CBT) is the “best and most investigated,” Dr. Bartova said, but international clinical practice guidelines “lack consistency” regarding recommendations for psychotherapy.

To examine the use and impact of psychotherapy for MDD patients, the researchers studied 1,410 adult inpatients and outpatients from 10 centers in eight countries who were surveyed between 2011 and 2016 by the European Group for the Study of Resistant Depression.

Participants were assessed via the Mini–International Neuropsychiatric Interview, the Montgomery-Åsberg Depression Rating Scale, and the Hamilton Depression Rating Scale.

Results showed that among 1,279 MDD patients who were included in the final analysis, 880 (68.8%) received only antidepressants, while 399 (31.2%) received some form of structured psychotherapy as part of their treatment.

These patients included 22.8% who received CBT, 3.4% who underwent psychoanalytic psychotherapy, and 1.3% who received systemic psychotherapy. The additional psychotherapy was not specified for 3.8%.

Dr. Bartova explained that the use of psychotherapy in combination pharmacologic treatment was significantly associated with younger age, higher educational attainment, and ongoing employment in comparison with antidepressant use alone (P < .001 for all).

In addition, combination therapy was associated with an earlier average age of MDD onset, lower severity of current depressive symptoms, a lower risk of suicidality, higher rates of additional melancholic features in the patients’ symptomatology, and higher rates of comorbid asthma and migraine (P < .001 for all).

There was also a significant association between the use of psychotherapy plus pharmacologic treatment and lower average daily doses of first-line antidepressant medication (P < .001), as well as more frequent administration of agomelatine (P < .001) and a trend toward greater use of vortioxetine (P = .006).

In contrast, among patients who received antidepressants alone, there was a trend toward higher rates of additional psychotic features (P = .054), and the patients were more likely to have received selective serotonin reuptake inhibitors as their first-line antidepressant medication (P < .001).

The researchers found there was no significant difference in rates of response, nonresponse, and treatment-resistant depression (TRD) between patients who received combination psychotherapy and pharmacotherapy and those who received antidepressants alone (P = .369).

Dr. Bartova showed that 25.8% of MDD patients who received combination therapy were classified as responders, compared with 23.5% of those given only antidepressants. Nonresponse was identified in 35.6% and 33.8% of patients, respectively, while 38.6% versus 42.7% had TRD.

Dr. Bartova and colleagues performed an additional analysis to determine whether there was any difference in response depending on the type of psychotherapy.

They divided patients who received combination therapy into those who had received CBT and those who had been given another form of psychotherapy.

Again, there were no significant differences in response, nonresponse, and TRD (P = .256). The response rate was 27.1% among patients given combination CBT, versus 22.4% among those who received another psychotherapy.

“Despite clinical guidelines and studies which advocate for psychotherapy and combining psychotherapy with antidepressants, this study shows that in real life, no added value can be demonstrated for psychotherapy in those already treated with antidepressants for severe depression,” Livia De Picker, MD, PhD, Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Belgium, said in the press release.

“This doesn’t necessarily mean that psychotherapy is not useful, but it is a clear sign that the way we are currently managing these depressed patients with psychotherapy is not effective and needs critical evaluation,” added Dr. De Picker, who was not involved in the research.

However, Michael E. Thase, MD, professor of psychiatry, University of Pennsylvania, Philadelphia, told this news organization that the current study “is a secondary analysis of a naturalistic study.”

A version of this article first appeared on Medscape.com.

Adding psychotherapy to pharmacologic treatment does not appear to improve treatment outcomes for patients with major depression, new research suggests.

Results of a cross-sectional, naturalistic, multicenter European study showed there were no significant differences in response rates between patients with major depressive disorder (MDD) who received combination treatment with psychotherapy and antidepressant medication in comparison with those who received antidepressant monotherapy, even when comparing different types of psychotherapy.

This “might emphasize the fundamental role of the underlying complex biological interrelationships in MDD and its treatment,” said study investigator Lucie Bartova, MD, PhD, Clinical Division of General Psychiatry, Medical University of Vienna.

However, she noted that patients who received psychotherapy in combination with antidepressants also had “beneficial sociodemographic and clinical characteristics,” which might reflect poorer access to “psychotherapeutic techniques for patients who are more severely ill and have less socioeconomic privilege.”

The resulting selection bias may cause patients with more severe illness to “fall by the wayside,” Dr. Bartova said.

Lead researcher Siegfried Kasper, MD, also from the Medical University of Vienna, agreed, saying in a press release that, by implication, “additional psychotherapy tends to be given to more highly educated and healthier patients, which may reflect the greater availability of psychotherapy to more socially and economically advantaged patients.”

The findings, some of which were previously published in the Journal of Psychiatry Research, were presented at the virtual European Psychiatric Association 2022 Congress.
 

Inconsistent guidelines

During her presentation, Dr. Bartova said that while “numerous effective antidepressant strategies are available for the treatment of MDD, many patients do not achieve a satisfactory treatment response,” which often leads to further management refinement and the use of off-label treatments.

She continued, saying that the “most obvious” approach in these situations is to try the available treatment options in a “systematic and individualized” manner, ideally by following recommended treatment algorithms.

Meta-analyses have suggested that standardized psychotherapy with fixed, regular sessions that follows an established rationale and is based on a defined school of thought is effective in MDD, “with at least moderate effects.”

Among the psychotherapy approaches, cognitive-behavioral therapy (CBT) is the “best and most investigated,” Dr. Bartova said, but international clinical practice guidelines “lack consistency” regarding recommendations for psychotherapy.

To examine the use and impact of psychotherapy for MDD patients, the researchers studied 1,410 adult inpatients and outpatients from 10 centers in eight countries who were surveyed between 2011 and 2016 by the European Group for the Study of Resistant Depression.

Participants were assessed via the Mini–International Neuropsychiatric Interview, the Montgomery-Åsberg Depression Rating Scale, and the Hamilton Depression Rating Scale.

Results showed that among 1,279 MDD patients who were included in the final analysis, 880 (68.8%) received only antidepressants, while 399 (31.2%) received some form of structured psychotherapy as part of their treatment.

These patients included 22.8% who received CBT, 3.4% who underwent psychoanalytic psychotherapy, and 1.3% who received systemic psychotherapy. The additional psychotherapy was not specified for 3.8%.

Dr. Bartova explained that the use of psychotherapy in combination pharmacologic treatment was significantly associated with younger age, higher educational attainment, and ongoing employment in comparison with antidepressant use alone (P < .001 for all).

In addition, combination therapy was associated with an earlier average age of MDD onset, lower severity of current depressive symptoms, a lower risk of suicidality, higher rates of additional melancholic features in the patients’ symptomatology, and higher rates of comorbid asthma and migraine (P < .001 for all).

There was also a significant association between the use of psychotherapy plus pharmacologic treatment and lower average daily doses of first-line antidepressant medication (P < .001), as well as more frequent administration of agomelatine (P < .001) and a trend toward greater use of vortioxetine (P = .006).

In contrast, among patients who received antidepressants alone, there was a trend toward higher rates of additional psychotic features (P = .054), and the patients were more likely to have received selective serotonin reuptake inhibitors as their first-line antidepressant medication (P < .001).

The researchers found there was no significant difference in rates of response, nonresponse, and treatment-resistant depression (TRD) between patients who received combination psychotherapy and pharmacotherapy and those who received antidepressants alone (P = .369).

Dr. Bartova showed that 25.8% of MDD patients who received combination therapy were classified as responders, compared with 23.5% of those given only antidepressants. Nonresponse was identified in 35.6% and 33.8% of patients, respectively, while 38.6% versus 42.7% had TRD.

Dr. Bartova and colleagues performed an additional analysis to determine whether there was any difference in response depending on the type of psychotherapy.

They divided patients who received combination therapy into those who had received CBT and those who had been given another form of psychotherapy.

Again, there were no significant differences in response, nonresponse, and TRD (P = .256). The response rate was 27.1% among patients given combination CBT, versus 22.4% among those who received another psychotherapy.

“Despite clinical guidelines and studies which advocate for psychotherapy and combining psychotherapy with antidepressants, this study shows that in real life, no added value can be demonstrated for psychotherapy in those already treated with antidepressants for severe depression,” Livia De Picker, MD, PhD, Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Belgium, said in the press release.

“This doesn’t necessarily mean that psychotherapy is not useful, but it is a clear sign that the way we are currently managing these depressed patients with psychotherapy is not effective and needs critical evaluation,” added Dr. De Picker, who was not involved in the research.

However, Michael E. Thase, MD, professor of psychiatry, University of Pennsylvania, Philadelphia, told this news organization that the current study “is a secondary analysis of a naturalistic study.”

A version of this article first appeared on Medscape.com.