MDedge Neurology

COPENHAGEN — Growing evidence supports the use of highly effective disease-modifying therapies for children with multiple sclerosis (MS). However, only few of these medications are licensed for pediatric use, indicating it may be time to reconsider the standard treatment approach for this patient population.

Treatments for pediatric-onset MS have mostly been used off-label until the recent approvals of fingolimod, dimethyl fumarate, and teriflunomide. Typically, children with MS start with moderately effective therapies, while more potent options are reserved for those who don’t respond.

However, recent research suggests this may not be the most effective treatment strategy for this patient population. Several studies suggesting impressive treatment responses to highly effective therapies (HETs) in children were presented at the 2024 ECTRIMS annual meeting.

In one study, initiating monoclonal antibody treatment during childhood was associated with reduced disability into early adulthood and beyond.

“Our findings are a strong argument for rethinking current treatment guidelines,” said study investigator Sifat Sharmin, PhD, The University of Melbourne, Australia.

“By allowing earlier access to highly effective treatments, we can significantly enhance the quality of life for children with MS and reduce the burden of long-term disability,” she added.

In another presentation, Yael Hacohen, MD, Great Ormond Street Hospital, London, England, noted that the use of these more effective monoclonal antibody therapies in children with MS has been associated with some improvements in Expanded Disability Status Scale (EDSS) scores after 2 or 3 years of treatment.

Maybe this is a sign that “this is a population that can repair, in contrast to adult patients,” she wondered.

MS is primarily a disease of adults, but pediatric MS accounts for up to 5% of all cases. Children with MS tend to have much more active disease than adults, Dr. Hacohen explained. However, they also tend to recover from attacks more quickly with little disability, which sometimes causes diagnostic delays.

A pediatrician or family doctor will often dismiss pins and needles or blurred vision that only lasts a couple of days and won’t send the patient for an MRI, she said. But on MRI, pediatric patients with MS often have multiple lesions, even though they may have had very few symptoms. The EDSS may not change very much, but there can still be significant brain atrophy.

Over the past 20 years, there’s been an explosion of new disease-modifying treatments for MS, but these high-efficacy treatments, such as antibody therapies, are often not prescribed until the patient reaches the age of 18 years, both Dr. Sharmin and Dr. Hacohen pointed out.

“We need to get some of these medications approved for use in children,” Dr. Hacohen said.
 

Slowed Disability

In her presentation, Dr. Sharmin reported an observational study that included 282 patients younger than 18 years at MS onset identified from the French MS Registry, the Italian MS Register, and the Global MSBase Registry.

Of these, 110 (39%) had initiated therapy with ocrelizumab, rituximab, or natalizumab early in the disease course between ages 12 and 17 years and 172 (61%) had initiated treatment with one of these agents at ages 20-22 years.

The primary outcome was the difference in EDSS scores from baseline (at age 18 years) to ages 23-27 years between those who had started treatment with one of these agents early and those who had started late.

At the baseline of age 18 years, the median EDSS score was 1.5 in the early group and 1.3 in the late group. Median follow-up time was 10.8 years.

The data were adjusted for baseline differences in factors such as sex, age at symptom onset, time from onset to clinically definite MS, and the number of relapses (using inverse probability treatment weighting based on propensity scores).

Results showed that between ages 23 and 27 years, disability was a 0.57 step lower in the early group than in the late group. The mean absolute differences in EDSS from baseline were 0.40 in the early group and 0.95 in the late group. This benefit of early treatment persisted throughout the rest of the follow-up period.

The substantially lower risk of progressing to higher disability levels in the early treatment group was particularly evident in the moderate disability range, where further progression was reduced by up to 97%, Dr. Sharmin noted.

“Starting these highly effective therapies, before the onset of significant neurological impairments, appears crucial for preserving neurological function in children with relapsing-remitting MS over the long term,” she said.

These findings highlight the critical importance of early intervention in pediatric-onset MS, she concluded.

The researchers are planning further work to generate more evidence to support the proactive treatment of pediatric-onset MS, with a particular focus on assessing the long-term risks for immunosuppressive therapies in this population.
 

Ocrelizumab Experience in Children

Dr. Hacohen reported on a UK cohort of children with MS treated with ocrelizumab, with 66 patients having more than 12 months of follow-up. Of these, only four patients had relapses, and there was no evidence of disease activity in 94% patients.

“We’ve stopped doing relapse clinic because they really don’t relapse,” Dr. Hacohen reported.

“This has completely changed our practice in pediatric MS,” she said. Twice a year, patients come in to have pre-infusion bloods and clinical assessments and then return a month later for treatment.

“They only have to come to the hospital for 4 days a year, and the rest of the time, they can forget they have MS,” said Dr. Hacohen.

In terms of complications, one patient in the UK cohort developed enterovirus meningitis but recovered completely, and two patients had hypogammaglobulinemia and were changed to an extended interval or to a different agent.

Dr. Hacohen cautioned that hypogammaglobulinemia — a condition in which immunoglobulin levels are below normal — is “something that hypothetically we should maybe be more worried about in the pediatric population, particularly as these patients are more likely to be on anti-CD20 therapies for a much longer time.”

She said this complication tends to happen after about 4 or 5 years of treatment. “If we start seeing IgG levels dropping, we need to come up with a plan about extending the dosing interval. We need clinical trials to look at this.”

Dr. Hacohen also drew attention to the issue of vaccinations not being effective in patients on anti-CD20 antibody therapy, which could be a particular problem in children.

However, given that vaccinations do seem to be effective in patients taking natalizumab, pediatric patients with highly active disease could receive the drug for 3-6 months while receiving vaccines and then switched over to ocrelizumab, she said.

Giving natalizumab for such a short period is not believed to have a high risk of developing JCV antibodies, she added.

In another presentation, Brenda Banwell, MD, Johns Hopkins Children’s Center, Baltimore, reported new data from an early study (OPERETTA 1) with ocrelizumab in pediatric relapsing-remitting MS showing a safety profile similar to that observed in adults. The suggested dose is 300 mg for children under 35 kg and 600 mg for adults over 35 kg, administered every 24 weeks. These doses will be further investigated in the ongoing phase III OPERETTA 2 trial.

Dr. Sharmin received a postdoctoral fellowship from MS Australia. The OPERETTA studies were sponsored by F. Hoffmann-La Roche. Dr. Banwell served as a consultant to Roche. Dr. Hacohen reported no relevant disclosures.
 

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

COPENHAGEN — Growing evidence supports the use of highly effective disease-modifying therapies for children with multiple sclerosis (MS). However, only few of these medications are licensed for pediatric use, indicating it may be time to reconsider the standard treatment approach for this patient population.

Treatments for pediatric-onset MS have mostly been used off-label until the recent approvals of fingolimod, dimethyl fumarate, and teriflunomide. Typically, children with MS start with moderately effective therapies, while more potent options are reserved for those who don’t respond.

However, recent research suggests this may not be the most effective treatment strategy for this patient population. Several studies suggesting impressive treatment responses to highly effective therapies (HETs) in children were presented at the 2024 ECTRIMS annual meeting.

In one study, initiating monoclonal antibody treatment during childhood was associated with reduced disability into early adulthood and beyond.

“Our findings are a strong argument for rethinking current treatment guidelines,” said study investigator Sifat Sharmin, PhD, The University of Melbourne, Australia.

“By allowing earlier access to highly effective treatments, we can significantly enhance the quality of life for children with MS and reduce the burden of long-term disability,” she added.

In another presentation, Yael Hacohen, MD, Great Ormond Street Hospital, London, England, noted that the use of these more effective monoclonal antibody therapies in children with MS has been associated with some improvements in Expanded Disability Status Scale (EDSS) scores after 2 or 3 years of treatment.

Maybe this is a sign that “this is a population that can repair, in contrast to adult patients,” she wondered.

MS is primarily a disease of adults, but pediatric MS accounts for up to 5% of all cases. Children with MS tend to have much more active disease than adults, Dr. Hacohen explained. However, they also tend to recover from attacks more quickly with little disability, which sometimes causes diagnostic delays.

A pediatrician or family doctor will often dismiss pins and needles or blurred vision that only lasts a couple of days and won’t send the patient for an MRI, she said. But on MRI, pediatric patients with MS often have multiple lesions, even though they may have had very few symptoms. The EDSS may not change very much, but there can still be significant brain atrophy.

Over the past 20 years, there’s been an explosion of new disease-modifying treatments for MS, but these high-efficacy treatments, such as antibody therapies, are often not prescribed until the patient reaches the age of 18 years, both Dr. Sharmin and Dr. Hacohen pointed out.

“We need to get some of these medications approved for use in children,” Dr. Hacohen said.
 

Slowed Disability

In her presentation, Dr. Sharmin reported an observational study that included 282 patients younger than 18 years at MS onset identified from the French MS Registry, the Italian MS Register, and the Global MSBase Registry.

Of these, 110 (39%) had initiated therapy with ocrelizumab, rituximab, or natalizumab early in the disease course between ages 12 and 17 years and 172 (61%) had initiated treatment with one of these agents at ages 20-22 years.

The primary outcome was the difference in EDSS scores from baseline (at age 18 years) to ages 23-27 years between those who had started treatment with one of these agents early and those who had started late.

At the baseline of age 18 years, the median EDSS score was 1.5 in the early group and 1.3 in the late group. Median follow-up time was 10.8 years.

The data were adjusted for baseline differences in factors such as sex, age at symptom onset, time from onset to clinically definite MS, and the number of relapses (using inverse probability treatment weighting based on propensity scores).

Results showed that between ages 23 and 27 years, disability was a 0.57 step lower in the early group than in the late group. The mean absolute differences in EDSS from baseline were 0.40 in the early group and 0.95 in the late group. This benefit of early treatment persisted throughout the rest of the follow-up period.

The substantially lower risk of progressing to higher disability levels in the early treatment group was particularly evident in the moderate disability range, where further progression was reduced by up to 97%, Dr. Sharmin noted.

“Starting these highly effective therapies, before the onset of significant neurological impairments, appears crucial for preserving neurological function in children with relapsing-remitting MS over the long term,” she said.

These findings highlight the critical importance of early intervention in pediatric-onset MS, she concluded.

The researchers are planning further work to generate more evidence to support the proactive treatment of pediatric-onset MS, with a particular focus on assessing the long-term risks for immunosuppressive therapies in this population.
 

Ocrelizumab Experience in Children

Dr. Hacohen reported on a UK cohort of children with MS treated with ocrelizumab, with 66 patients having more than 12 months of follow-up. Of these, only four patients had relapses, and there was no evidence of disease activity in 94% patients.

“We’ve stopped doing relapse clinic because they really don’t relapse,” Dr. Hacohen reported.

“This has completely changed our practice in pediatric MS,” she said. Twice a year, patients come in to have pre-infusion bloods and clinical assessments and then return a month later for treatment.

“They only have to come to the hospital for 4 days a year, and the rest of the time, they can forget they have MS,” said Dr. Hacohen.

In terms of complications, one patient in the UK cohort developed enterovirus meningitis but recovered completely, and two patients had hypogammaglobulinemia and were changed to an extended interval or to a different agent.

Dr. Hacohen cautioned that hypogammaglobulinemia — a condition in which immunoglobulin levels are below normal — is “something that hypothetically we should maybe be more worried about in the pediatric population, particularly as these patients are more likely to be on anti-CD20 therapies for a much longer time.”

She said this complication tends to happen after about 4 or 5 years of treatment. “If we start seeing IgG levels dropping, we need to come up with a plan about extending the dosing interval. We need clinical trials to look at this.”

Dr. Hacohen also drew attention to the issue of vaccinations not being effective in patients on anti-CD20 antibody therapy, which could be a particular problem in children.

However, given that vaccinations do seem to be effective in patients taking natalizumab, pediatric patients with highly active disease could receive the drug for 3-6 months while receiving vaccines and then switched over to ocrelizumab, she said.

Giving natalizumab for such a short period is not believed to have a high risk of developing JCV antibodies, she added.

In another presentation, Brenda Banwell, MD, Johns Hopkins Children’s Center, Baltimore, reported new data from an early study (OPERETTA 1) with ocrelizumab in pediatric relapsing-remitting MS showing a safety profile similar to that observed in adults. The suggested dose is 300 mg for children under 35 kg and 600 mg for adults over 35 kg, administered every 24 weeks. These doses will be further investigated in the ongoing phase III OPERETTA 2 trial.

Dr. Sharmin received a postdoctoral fellowship from MS Australia. The OPERETTA studies were sponsored by F. Hoffmann-La Roche. Dr. Banwell served as a consultant to Roche. Dr. Hacohen reported no relevant disclosures.
 

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

COPENHAGEN — Growing evidence supports the use of highly effective disease-modifying therapies for children with multiple sclerosis (MS). However, only few of these medications are licensed for pediatric use, indicating it may be time to reconsider the standard treatment approach for this patient population.

Treatments for pediatric-onset MS have mostly been used off-label until the recent approvals of fingolimod, dimethyl fumarate, and teriflunomide. Typically, children with MS start with moderately effective therapies, while more potent options are reserved for those who don’t respond.

However, recent research suggests this may not be the most effective treatment strategy for this patient population. Several studies suggesting impressive treatment responses to highly effective therapies (HETs) in children were presented at the 2024 ECTRIMS annual meeting.

In one study, initiating monoclonal antibody treatment during childhood was associated with reduced disability into early adulthood and beyond.

“Our findings are a strong argument for rethinking current treatment guidelines,” said study investigator Sifat Sharmin, PhD, The University of Melbourne, Australia.

“By allowing earlier access to highly effective treatments, we can significantly enhance the quality of life for children with MS and reduce the burden of long-term disability,” she added.

In another presentation, Yael Hacohen, MD, Great Ormond Street Hospital, London, England, noted that the use of these more effective monoclonal antibody therapies in children with MS has been associated with some improvements in Expanded Disability Status Scale (EDSS) scores after 2 or 3 years of treatment.

Maybe this is a sign that “this is a population that can repair, in contrast to adult patients,” she wondered.

MS is primarily a disease of adults, but pediatric MS accounts for up to 5% of all cases. Children with MS tend to have much more active disease than adults, Dr. Hacohen explained. However, they also tend to recover from attacks more quickly with little disability, which sometimes causes diagnostic delays.

A pediatrician or family doctor will often dismiss pins and needles or blurred vision that only lasts a couple of days and won’t send the patient for an MRI, she said. But on MRI, pediatric patients with MS often have multiple lesions, even though they may have had very few symptoms. The EDSS may not change very much, but there can still be significant brain atrophy.

Over the past 20 years, there’s been an explosion of new disease-modifying treatments for MS, but these high-efficacy treatments, such as antibody therapies, are often not prescribed until the patient reaches the age of 18 years, both Dr. Sharmin and Dr. Hacohen pointed out.

“We need to get some of these medications approved for use in children,” Dr. Hacohen said.
 

Slowed Disability

In her presentation, Dr. Sharmin reported an observational study that included 282 patients younger than 18 years at MS onset identified from the French MS Registry, the Italian MS Register, and the Global MSBase Registry.

Of these, 110 (39%) had initiated therapy with ocrelizumab, rituximab, or natalizumab early in the disease course between ages 12 and 17 years and 172 (61%) had initiated treatment with one of these agents at ages 20-22 years.

The primary outcome was the difference in EDSS scores from baseline (at age 18 years) to ages 23-27 years between those who had started treatment with one of these agents early and those who had started late.

At the baseline of age 18 years, the median EDSS score was 1.5 in the early group and 1.3 in the late group. Median follow-up time was 10.8 years.

The data were adjusted for baseline differences in factors such as sex, age at symptom onset, time from onset to clinically definite MS, and the number of relapses (using inverse probability treatment weighting based on propensity scores).

Results showed that between ages 23 and 27 years, disability was a 0.57 step lower in the early group than in the late group. The mean absolute differences in EDSS from baseline were 0.40 in the early group and 0.95 in the late group. This benefit of early treatment persisted throughout the rest of the follow-up period.

The substantially lower risk of progressing to higher disability levels in the early treatment group was particularly evident in the moderate disability range, where further progression was reduced by up to 97%, Dr. Sharmin noted.

“Starting these highly effective therapies, before the onset of significant neurological impairments, appears crucial for preserving neurological function in children with relapsing-remitting MS over the long term,” she said.

These findings highlight the critical importance of early intervention in pediatric-onset MS, she concluded.

The researchers are planning further work to generate more evidence to support the proactive treatment of pediatric-onset MS, with a particular focus on assessing the long-term risks for immunosuppressive therapies in this population.
 

Ocrelizumab Experience in Children

Dr. Hacohen reported on a UK cohort of children with MS treated with ocrelizumab, with 66 patients having more than 12 months of follow-up. Of these, only four patients had relapses, and there was no evidence of disease activity in 94% patients.

“We’ve stopped doing relapse clinic because they really don’t relapse,” Dr. Hacohen reported.

“This has completely changed our practice in pediatric MS,” she said. Twice a year, patients come in to have pre-infusion bloods and clinical assessments and then return a month later for treatment.

“They only have to come to the hospital for 4 days a year, and the rest of the time, they can forget they have MS,” said Dr. Hacohen.

In terms of complications, one patient in the UK cohort developed enterovirus meningitis but recovered completely, and two patients had hypogammaglobulinemia and were changed to an extended interval or to a different agent.

Dr. Hacohen cautioned that hypogammaglobulinemia — a condition in which immunoglobulin levels are below normal — is “something that hypothetically we should maybe be more worried about in the pediatric population, particularly as these patients are more likely to be on anti-CD20 therapies for a much longer time.”

She said this complication tends to happen after about 4 or 5 years of treatment. “If we start seeing IgG levels dropping, we need to come up with a plan about extending the dosing interval. We need clinical trials to look at this.”

Dr. Hacohen also drew attention to the issue of vaccinations not being effective in patients on anti-CD20 antibody therapy, which could be a particular problem in children.

However, given that vaccinations do seem to be effective in patients taking natalizumab, pediatric patients with highly active disease could receive the drug for 3-6 months while receiving vaccines and then switched over to ocrelizumab, she said.

Giving natalizumab for such a short period is not believed to have a high risk of developing JCV antibodies, she added.

In another presentation, Brenda Banwell, MD, Johns Hopkins Children’s Center, Baltimore, reported new data from an early study (OPERETTA 1) with ocrelizumab in pediatric relapsing-remitting MS showing a safety profile similar to that observed in adults. The suggested dose is 300 mg for children under 35 kg and 600 mg for adults over 35 kg, administered every 24 weeks. These doses will be further investigated in the ongoing phase III OPERETTA 2 trial.

Dr. Sharmin received a postdoctoral fellowship from MS Australia. The OPERETTA studies were sponsored by F. Hoffmann-La Roche. Dr. Banwell served as a consultant to Roche. Dr. Hacohen reported no relevant disclosures.
 

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

PHILADELPHIA — The investigational agent ecopipam reduces tic severity in children and adolescents with Tourette syndrome without exacerbating common psychiatric comorbidities, results of a new analysis suggest.

As previously reported, the first-in-class dopamine-1 (D1) receptor antagonist reduced the primary endpoint of tic severity scores by 30% compared with placebo among 149 patients in the 12-week, phase 2b D1AMOND trial. 

What was unknown, however, is whether ecopipam would affect the comorbidities of attention-deficit/hyperactivity disorder (ADHD), anxiety, obsessive-compulsive disorder (OCD), and depression that were present in two thirds of participants.

The two key findings in this post hoc analysis were “first, that patients with a nonmotor diagnosis like depression or ADHD did not do any worse in terms of tic efficacy; and second, we didn’t find any evidence that any of the nonmotor symptoms of Tourette’s got worse with ecopipam,” said study investigator Donald Gilbert, MD, professor of pediatrics and neurology at University of Cincinnati Children’s Hospital Medical Center.

Dr. Gilbert presented the results at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2024. 
 

No Worsening of ADHD Symptoms

Tourette syndrome affects approximately 1 in 160 children between 5 and 17 years of age in the United States, data from the Tourette Association of America show. Research has shown that 85% of patients with Tourette syndrome will have a co-occurring psychiatric condition. 

Guidelines recommend Comprehensive Behavioral Intervention for Tics (CBIT) as first-line treatment for Tourette syndrome, but cost and access are barriers. The only currently approved medications to treat Tourette syndrome are antipsychotics that act on the D2 receptor, but their use is limited by the potential for weight gain, metabolic changes, drug-induced movement disorders, and risk for suicidality, said Dr. Gilbert. 

The D1AMOND study randomly assigned patients aged 6-17 years with Tourette syndrome and a Yale Global Tic Severity Total Tic Scale score of at least 20 to receive a target steady-state dose of 2 mg/kg/d of oral ecopipam or placebo for a 4-week titration period, followed by an 8-week treatment phase before being tapered off the study drug. 

Patients were allowed to remain on medications without D2-receptor blocking activity for anxiety, OCD, and ADHD if the dosage was stable for 4 weeks before screening and not specifically prescribed for tics. 

A mixed model for repeated measures was used to assess changes in several scales administered at baseline and at weeks 4, 6, 8, and 12: the Swanson, Nolan, and Pelham Teacher and Parent Rating Scale (SNAP-IV); Pediatric Anxiety Rating Scale; Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), and Children’s Depression Rating Scale–Revised (CDRS-R). 

In patients with a co-occurring psychiatric condition, no significant differences were found over time between ecopipam and placebo in terms of SNAP-IV (-4.4; P = .45), Pediatric Anxiety Rating Scale (1.0; P = .62), CDRS-R (-3.2; P = .65), or CY-BOCS (-0.7; P = .76) scores.

For ADHD, the most frequent comorbidity, scores trended lower in the ecopipam group but were not significantly different from those in the placebo group. “We found no evidence that ecopipam worsened ADHD symptoms,” Dr. Gilbert said.
 

No Weight Gain

Suicidal ideation was reported during the dosing period in eight patients in the placebo group and none in the ecopipam group. One patient treated with ecopipam had multiple depressive episodes and dropped out of the study on day 79. Ecopipam was discontinued in another patient because of anxiety. 

Notably, there was more weight gain in the placebo group than in the ecopipam group (2.4 kg vs 1.8 kg) by 12 weeks. No shifts from baseline were seen in blood glucose, A1c, total cholesterol, or triglycerides in either group. 

The lack of weight gain with ecopipam is important, Dr. Gilbert stressed. “Medicines that block D2 so often cause weight gain, and a lot of our patients, unfortunately, can be heavier already,” he explained. “We don’t want to make that worse or put them at a long-term risk of type 2 diabetes.”  

For patients with more severe disease, we really “do need something else besides D2-blockers in our tool kit,” he added. 

Commenting on the study, Tanya Simuni, MD, co-moderator of the session and director of the Parkinson’s Disease and Movement Disorders Center, Northwestern Feinberg School of Medicine, Chicago, said the aim of assessing D1-directed medications is to reduce the negative impact of traditional antipsychotics with a theoretical benefit on hyperkinetic movement.

But the most important thing that they’ve shown is that “there was no negative effect, no liability for the nonmotor manifestations of Tourette’s. That is important because Tourette’s is not a pure motor syndrome, and psychiatric manifestations in a lot of cases are associated with more disease-related quality of life impairment compared to the motor manifestations,” said Dr. Simuni.

That said, she noted, the “ideal drug would be the one that would have benefit for both motor and nonmotor domains.” 
 

Multiple Agents in the Pipeline 

“The neuropharmacology of Tourette syndrome has long remained stagnant, and most existing treatments often fail to balance efficacy with tolerability, underscoring the urgent need for newer therapeutics,” Christos Ganos, MD, professor of neurology, University of Toronto, said in a press release.

He noted that three studies have been published on ecopipam since 2014: an 8-week, open-label trial in adults with Tourette syndrome, a 4-week, placebo-controlled crossover trial in 38 children with Tourette syndrome, and the 12-week D1AMOND trial.

“These studies demonstrated clinically meaningful reductions in tics, without relevant safety concerns or changes in Tourette syndrome-typical neuropsychiatric measures, as also shown by the abstract highlighted here,” Dr. Ganos said. 

“This emerging body of research provides a solid foundation for introducing ecopipam as a novel pharmacological agent to treat tics and may motivate further work, both on the pathophysiology and pharmacotherapy of tic disorders and their associations.”

A single-arm, phase 3 trial is currently underway at 58 centers in North America and Europe investigating the long-term safety and tolerability of ecopipam over 24 months in 150 children, adolescents, and adults with Tourette syndrome. The study is expected to be completed in 2027.

Several other new medications are also under investigation including the vesicular monoamine transporter (VMAT2) inhibitors tetrabenazine, deutetrabenazine, and valbenazine; the PEDE10A inhibitor gemlapodect; the allopregnanolone antagonist sepranolone; and SCI-110, which combines dronabinol (the synthetic form of tetrahydrocannabinol) and the endocannabinoid palmitoylethanolamide.

The study was funded by Emalex Biosciences. Dr. Gilbert’s institution received research support from Emalex Biosciences and PTC Therapeutics. Dr. Gilbert has received publishing royalties from a healthcare-related publication; compensation for serving as a medical expert with Teladoc; Advanced Medical; and the National Vaccine Injury Compensation Program, US Department of Health and Human Services. Simuni reports no relevant conflicts of interest. Dr. Ganos has received honoraria for educational activities from the Movement Disorder Society and academic research support from VolkswagenStiftung. 
 

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

PHILADELPHIA — The investigational agent ecopipam reduces tic severity in children and adolescents with Tourette syndrome without exacerbating common psychiatric comorbidities, results of a new analysis suggest.

As previously reported, the first-in-class dopamine-1 (D1) receptor antagonist reduced the primary endpoint of tic severity scores by 30% compared with placebo among 149 patients in the 12-week, phase 2b D1AMOND trial. 

What was unknown, however, is whether ecopipam would affect the comorbidities of attention-deficit/hyperactivity disorder (ADHD), anxiety, obsessive-compulsive disorder (OCD), and depression that were present in two thirds of participants.

The two key findings in this post hoc analysis were “first, that patients with a nonmotor diagnosis like depression or ADHD did not do any worse in terms of tic efficacy; and second, we didn’t find any evidence that any of the nonmotor symptoms of Tourette’s got worse with ecopipam,” said study investigator Donald Gilbert, MD, professor of pediatrics and neurology at University of Cincinnati Children’s Hospital Medical Center.

Dr. Gilbert presented the results at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2024. 
 

No Worsening of ADHD Symptoms

Tourette syndrome affects approximately 1 in 160 children between 5 and 17 years of age in the United States, data from the Tourette Association of America show. Research has shown that 85% of patients with Tourette syndrome will have a co-occurring psychiatric condition. 

Guidelines recommend Comprehensive Behavioral Intervention for Tics (CBIT) as first-line treatment for Tourette syndrome, but cost and access are barriers. The only currently approved medications to treat Tourette syndrome are antipsychotics that act on the D2 receptor, but their use is limited by the potential for weight gain, metabolic changes, drug-induced movement disorders, and risk for suicidality, said Dr. Gilbert. 

The D1AMOND study randomly assigned patients aged 6-17 years with Tourette syndrome and a Yale Global Tic Severity Total Tic Scale score of at least 20 to receive a target steady-state dose of 2 mg/kg/d of oral ecopipam or placebo for a 4-week titration period, followed by an 8-week treatment phase before being tapered off the study drug. 

Patients were allowed to remain on medications without D2-receptor blocking activity for anxiety, OCD, and ADHD if the dosage was stable for 4 weeks before screening and not specifically prescribed for tics. 

A mixed model for repeated measures was used to assess changes in several scales administered at baseline and at weeks 4, 6, 8, and 12: the Swanson, Nolan, and Pelham Teacher and Parent Rating Scale (SNAP-IV); Pediatric Anxiety Rating Scale; Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), and Children’s Depression Rating Scale–Revised (CDRS-R). 

In patients with a co-occurring psychiatric condition, no significant differences were found over time between ecopipam and placebo in terms of SNAP-IV (-4.4; P = .45), Pediatric Anxiety Rating Scale (1.0; P = .62), CDRS-R (-3.2; P = .65), or CY-BOCS (-0.7; P = .76) scores.

For ADHD, the most frequent comorbidity, scores trended lower in the ecopipam group but were not significantly different from those in the placebo group. “We found no evidence that ecopipam worsened ADHD symptoms,” Dr. Gilbert said.
 

No Weight Gain

Suicidal ideation was reported during the dosing period in eight patients in the placebo group and none in the ecopipam group. One patient treated with ecopipam had multiple depressive episodes and dropped out of the study on day 79. Ecopipam was discontinued in another patient because of anxiety. 

Notably, there was more weight gain in the placebo group than in the ecopipam group (2.4 kg vs 1.8 kg) by 12 weeks. No shifts from baseline were seen in blood glucose, A1c, total cholesterol, or triglycerides in either group. 

The lack of weight gain with ecopipam is important, Dr. Gilbert stressed. “Medicines that block D2 so often cause weight gain, and a lot of our patients, unfortunately, can be heavier already,” he explained. “We don’t want to make that worse or put them at a long-term risk of type 2 diabetes.”  

For patients with more severe disease, we really “do need something else besides D2-blockers in our tool kit,” he added. 

Commenting on the study, Tanya Simuni, MD, co-moderator of the session and director of the Parkinson’s Disease and Movement Disorders Center, Northwestern Feinberg School of Medicine, Chicago, said the aim of assessing D1-directed medications is to reduce the negative impact of traditional antipsychotics with a theoretical benefit on hyperkinetic movement.

But the most important thing that they’ve shown is that “there was no negative effect, no liability for the nonmotor manifestations of Tourette’s. That is important because Tourette’s is not a pure motor syndrome, and psychiatric manifestations in a lot of cases are associated with more disease-related quality of life impairment compared to the motor manifestations,” said Dr. Simuni.

That said, she noted, the “ideal drug would be the one that would have benefit for both motor and nonmotor domains.” 
 

Multiple Agents in the Pipeline 

“The neuropharmacology of Tourette syndrome has long remained stagnant, and most existing treatments often fail to balance efficacy with tolerability, underscoring the urgent need for newer therapeutics,” Christos Ganos, MD, professor of neurology, University of Toronto, said in a press release.

He noted that three studies have been published on ecopipam since 2014: an 8-week, open-label trial in adults with Tourette syndrome, a 4-week, placebo-controlled crossover trial in 38 children with Tourette syndrome, and the 12-week D1AMOND trial.

“These studies demonstrated clinically meaningful reductions in tics, without relevant safety concerns or changes in Tourette syndrome-typical neuropsychiatric measures, as also shown by the abstract highlighted here,” Dr. Ganos said. 

“This emerging body of research provides a solid foundation for introducing ecopipam as a novel pharmacological agent to treat tics and may motivate further work, both on the pathophysiology and pharmacotherapy of tic disorders and their associations.”

A single-arm, phase 3 trial is currently underway at 58 centers in North America and Europe investigating the long-term safety and tolerability of ecopipam over 24 months in 150 children, adolescents, and adults with Tourette syndrome. The study is expected to be completed in 2027.

Several other new medications are also under investigation including the vesicular monoamine transporter (VMAT2) inhibitors tetrabenazine, deutetrabenazine, and valbenazine; the PEDE10A inhibitor gemlapodect; the allopregnanolone antagonist sepranolone; and SCI-110, which combines dronabinol (the synthetic form of tetrahydrocannabinol) and the endocannabinoid palmitoylethanolamide.

The study was funded by Emalex Biosciences. Dr. Gilbert’s institution received research support from Emalex Biosciences and PTC Therapeutics. Dr. Gilbert has received publishing royalties from a healthcare-related publication; compensation for serving as a medical expert with Teladoc; Advanced Medical; and the National Vaccine Injury Compensation Program, US Department of Health and Human Services. Simuni reports no relevant conflicts of interest. Dr. Ganos has received honoraria for educational activities from the Movement Disorder Society and academic research support from VolkswagenStiftung. 
 

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

PHILADELPHIA — The investigational agent ecopipam reduces tic severity in children and adolescents with Tourette syndrome without exacerbating common psychiatric comorbidities, results of a new analysis suggest.

As previously reported, the first-in-class dopamine-1 (D1) receptor antagonist reduced the primary endpoint of tic severity scores by 30% compared with placebo among 149 patients in the 12-week, phase 2b D1AMOND trial. 

What was unknown, however, is whether ecopipam would affect the comorbidities of attention-deficit/hyperactivity disorder (ADHD), anxiety, obsessive-compulsive disorder (OCD), and depression that were present in two thirds of participants.

The two key findings in this post hoc analysis were “first, that patients with a nonmotor diagnosis like depression or ADHD did not do any worse in terms of tic efficacy; and second, we didn’t find any evidence that any of the nonmotor symptoms of Tourette’s got worse with ecopipam,” said study investigator Donald Gilbert, MD, professor of pediatrics and neurology at University of Cincinnati Children’s Hospital Medical Center.

Dr. Gilbert presented the results at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2024. 
 

No Worsening of ADHD Symptoms

Tourette syndrome affects approximately 1 in 160 children between 5 and 17 years of age in the United States, data from the Tourette Association of America show. Research has shown that 85% of patients with Tourette syndrome will have a co-occurring psychiatric condition. 

Guidelines recommend Comprehensive Behavioral Intervention for Tics (CBIT) as first-line treatment for Tourette syndrome, but cost and access are barriers. The only currently approved medications to treat Tourette syndrome are antipsychotics that act on the D2 receptor, but their use is limited by the potential for weight gain, metabolic changes, drug-induced movement disorders, and risk for suicidality, said Dr. Gilbert. 

The D1AMOND study randomly assigned patients aged 6-17 years with Tourette syndrome and a Yale Global Tic Severity Total Tic Scale score of at least 20 to receive a target steady-state dose of 2 mg/kg/d of oral ecopipam or placebo for a 4-week titration period, followed by an 8-week treatment phase before being tapered off the study drug. 

Patients were allowed to remain on medications without D2-receptor blocking activity for anxiety, OCD, and ADHD if the dosage was stable for 4 weeks before screening and not specifically prescribed for tics. 

A mixed model for repeated measures was used to assess changes in several scales administered at baseline and at weeks 4, 6, 8, and 12: the Swanson, Nolan, and Pelham Teacher and Parent Rating Scale (SNAP-IV); Pediatric Anxiety Rating Scale; Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), and Children’s Depression Rating Scale–Revised (CDRS-R). 

In patients with a co-occurring psychiatric condition, no significant differences were found over time between ecopipam and placebo in terms of SNAP-IV (-4.4; P = .45), Pediatric Anxiety Rating Scale (1.0; P = .62), CDRS-R (-3.2; P = .65), or CY-BOCS (-0.7; P = .76) scores.

For ADHD, the most frequent comorbidity, scores trended lower in the ecopipam group but were not significantly different from those in the placebo group. “We found no evidence that ecopipam worsened ADHD symptoms,” Dr. Gilbert said.
 

No Weight Gain

Suicidal ideation was reported during the dosing period in eight patients in the placebo group and none in the ecopipam group. One patient treated with ecopipam had multiple depressive episodes and dropped out of the study on day 79. Ecopipam was discontinued in another patient because of anxiety. 

Notably, there was more weight gain in the placebo group than in the ecopipam group (2.4 kg vs 1.8 kg) by 12 weeks. No shifts from baseline were seen in blood glucose, A1c, total cholesterol, or triglycerides in either group. 

The lack of weight gain with ecopipam is important, Dr. Gilbert stressed. “Medicines that block D2 so often cause weight gain, and a lot of our patients, unfortunately, can be heavier already,” he explained. “We don’t want to make that worse or put them at a long-term risk of type 2 diabetes.”  

For patients with more severe disease, we really “do need something else besides D2-blockers in our tool kit,” he added. 

Commenting on the study, Tanya Simuni, MD, co-moderator of the session and director of the Parkinson’s Disease and Movement Disorders Center, Northwestern Feinberg School of Medicine, Chicago, said the aim of assessing D1-directed medications is to reduce the negative impact of traditional antipsychotics with a theoretical benefit on hyperkinetic movement.

But the most important thing that they’ve shown is that “there was no negative effect, no liability for the nonmotor manifestations of Tourette’s. That is important because Tourette’s is not a pure motor syndrome, and psychiatric manifestations in a lot of cases are associated with more disease-related quality of life impairment compared to the motor manifestations,” said Dr. Simuni.

That said, she noted, the “ideal drug would be the one that would have benefit for both motor and nonmotor domains.” 
 

Multiple Agents in the Pipeline 

“The neuropharmacology of Tourette syndrome has long remained stagnant, and most existing treatments often fail to balance efficacy with tolerability, underscoring the urgent need for newer therapeutics,” Christos Ganos, MD, professor of neurology, University of Toronto, said in a press release.

He noted that three studies have been published on ecopipam since 2014: an 8-week, open-label trial in adults with Tourette syndrome, a 4-week, placebo-controlled crossover trial in 38 children with Tourette syndrome, and the 12-week D1AMOND trial.

“These studies demonstrated clinically meaningful reductions in tics, without relevant safety concerns or changes in Tourette syndrome-typical neuropsychiatric measures, as also shown by the abstract highlighted here,” Dr. Ganos said. 

“This emerging body of research provides a solid foundation for introducing ecopipam as a novel pharmacological agent to treat tics and may motivate further work, both on the pathophysiology and pharmacotherapy of tic disorders and their associations.”

A single-arm, phase 3 trial is currently underway at 58 centers in North America and Europe investigating the long-term safety and tolerability of ecopipam over 24 months in 150 children, adolescents, and adults with Tourette syndrome. The study is expected to be completed in 2027.

Several other new medications are also under investigation including the vesicular monoamine transporter (VMAT2) inhibitors tetrabenazine, deutetrabenazine, and valbenazine; the PEDE10A inhibitor gemlapodect; the allopregnanolone antagonist sepranolone; and SCI-110, which combines dronabinol (the synthetic form of tetrahydrocannabinol) and the endocannabinoid palmitoylethanolamide.

The study was funded by Emalex Biosciences. Dr. Gilbert’s institution received research support from Emalex Biosciences and PTC Therapeutics. Dr. Gilbert has received publishing royalties from a healthcare-related publication; compensation for serving as a medical expert with Teladoc; Advanced Medical; and the National Vaccine Injury Compensation Program, US Department of Health and Human Services. Simuni reports no relevant conflicts of interest. Dr. Ganos has received honoraria for educational activities from the Movement Disorder Society and academic research support from VolkswagenStiftung. 
 

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

Alzheimer’s disease (AD), the most common cause of dementia, is the fifth leading cause of death in the United States. An estimated 6.9 million Americans aged 65 years or older have AD. Comorbid conditions in AD may exacerbate the progression of dementia and negatively affect overall health.

Although the exact mechanisms remain unclear, systemic inflammation is thought to play a significant role in the development of many common comorbidities associated with AD. Among the most frequently observed comorbid conditions are hypertension, diabetes, and depression. The presence of these comorbidities affects the treatment and management of AD, underscoring the need to understand the mechanisms of their interrelationship and develop effective management strategies. 
 

Hypertension 

Hypertension is a well-established risk factor for numerous health conditions, including AD. A comprehensive review of five meta-analyses and 52 primary studies revealed that elevated systolic blood pressure (SBP) correlates with an 11 % increased risk of developing AD, raising the question of whether early intervention and control of blood pressure would mitigate the risk for AD later in life. 

Findings from the Northern Manhattan Study suggest that although elevated SBP contributes to cognitive decline in older patients, the use of antihypertensive medications can neutralize the effects of high SBP on certain cognitive functions. Furthermore, a systematic review and meta-analysis comprising 12 trials (92,135 participants) demonstrated a significant reduction in the risk for dementia and cognitive impairment with antihypertensive treatment.

Notably, a retrospective cohort study involving 69,081 participants treated with beta-blockers for hypertension found that beta-blockers with high blood-brain barrier permeability were associated with a reduced risk for AD compared with those with low blood-brain barrier permeability. Additionally, a secondary analysis of the SPRINT trial found antihypertensive medications that stimulate vs inhibit type 2 and 4 angiotensin II receptors were associated with a lower incidence of cognitive impairment. Although further clinical trials are necessary to directly assess specific medications, these findings emphasize the potential of antihypertensive treatment as a strategic approach to reduce the risk for AD.
 

Type 2 Diabetes 

The connection between AD and type 2 diabetes is such that AD is sometimes referred to as “type 3 diabetes.” Both diseases share some of the same underlying pathophysiologic mechanisms, particularly the development of insulin resistance and oxidative stress. A prospective cohort study of 10,095 participants showed that diabetes was significantly associated with a higher risk of developing dementia; this risk is even greater in patients who develop diabetes at an earlier age.

In an interview with this news organization, Alvaro Pascual-Leone, MD, PhD, a professor of neurology at Harvard Medical School, Boston, said, “In addition to being a comorbidity factor, diabetes appears to be a predisposing risk factor for AD.” This is supported by a comprehensive literature review showing an increased progression from mild cognitive impairment (MCI) to dementia in patients with diabetes, prediabetes, or metabolic syndrome, with a pooled odds ratio for dementia progression in individuals with diabetes of 1.53.

Owing to the overlapping pathophysiologic mechanisms in AD and diabetes, treating one condition may have beneficial effects on the other. A systematic umbrella review and meta-analysis that included 10 meta-analyses across nine classes of diabetes drugs found a protective effect against dementia with the use of metformin, thiazolidinediones (including pioglitazone), glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors. Moreover, a cohort study of 12,220 patients who discontinued metformin early (ie, stopped using metformin without a prior history of abnormal kidney function) and 29,126 patients considered routine users found an increased risk for dementia in the early terminator group. Although further research is warranted, the concurrent treatment of AD and diabetes with antidiabetic agents holds considerable promise.
 

Depression and Anxiety

Anxiety and depression are significant risk factors for AD, and conversely, AD increases the likelihood of developing these psychiatric conditions. A systematic review of 14,760 studies showed dysthymia often emerges during the early stages of AD as an emotional response to cognitive decline. 

Data from the Australian Imaging Biomarkers and Lifestyle study showed a markedly elevated risk for AD and MCI among individuals with preexisting anxiety or depression. This study also found that age, sex, and marital status are important determinants, with men and single individuals with depression being particularly susceptible to developing AD. Conversely, a cohort study of 129,410 AD patients with AD, 390,088 patients with all-cause dementia, and 3,900,880 age-matched controls without a history of depression showed a cumulative incidence of depression of 13% in the AD group vs 3% in the control group, suggesting a heightened risk for depression following an AD diagnosis. 

These findings underscore the importance of targeted screening and assessment for patients with anxiety and depression who may be at risk for AD or those diagnosed with AD who are at risk for subsequent depression and anxiety. Although antidepressants are effective in treating depression in general, their efficacy in AD-related depression is of variable quality, probably owing to differing pathophysiologic mechanisms of the disease. Further research is necessary to explore both pharmacologic and nonpharmacologic interventions for treating depression in AD patients. Some studies have found that cognitive behavioral-therapy can be effective in improving depression in patients with AD.
 

Sleep Disorders

Research has shown a strong correlation between AD and sleep disorders, particularly obstructive sleep apnea, insomnia, and circadian rhythm disruptions. Additionally, studies suggest that insomnia and sleep deprivation contribute to increased amyloid beta production and tau pathology, hallmark features of AD. A scoping review of 70 studies proposed that this relationship is mediated by the glymphatic system (glial-dependent waste clearance pathway in the central nervous system), and that sleep deprivation disrupts its function, leading to protein accumulation and subsequent neurologic symptoms of AD. Another study showed that sleep deprivation triggers glial cell activation, initiating an inflammatory cascade that accelerates AD progression.

Given that the gold standard treatment for obstructive sleep apnea is continuous positive airway pressure (CPAP), it has been hypothesized that CPAP could also alleviate AD symptoms owing to shared pathophysiologic mechanisms of these conditions. A large systemic review found that CPAP use improved AD symptoms in patients with mild AD or MCI, though other sleep interventions, such as cognitive-behavioral therapy and melatonin supplementation, have yielded mixed outcomes. However, most studies in this area are small in scale, and there remains a paucity of research on treating sleep disorders in AD patients, indicating a need for further investigation.
 

Musculoskeletal Disorders

Although no direct causative link has been established, research indicates an association between osteoarthritis (OA) and dementia, likely because of similar pathophysiologic mechanisms, including systemic inflammation. Longitudinal analyses of data from the Alzheimer’s Disease Neuroimaging Initiative study found cognitively normal older individuals with OA experience more rapid declines in hippocampal volumes compared to those without OA, suggesting that OA may elevate the risk of cognitive impairment. Current treatments for OA, such as nonsteroidal anti-inflammatory drugs, glucocorticoids, and disease-modifying OA drugs, might also help alleviate AD symptoms related to inflammation, though the research in this area is limited.

AD has also been linked to osteoporosis. In a longitudinal follow-up study involving 78,994 patients with osteoporosis and 78,994 controls, AD developed in 5856 patients with osteoporosis compared with 3761 patients in the control group. These findings represent a 1.27-fold higher incidence of AD in patients with osteoporosis than in the control group, suggesting that osteoporosis might be a risk factor for AD.

Additionally, research has identified a relationship between AD and increased fracture risk and decreased bone mineral density, with AD patients exhibiting a significantly higher likelihood of bone fractures compared with those without AD. “Falls and fractures, aside from the risk they pose in all geriatric patients, in individuals with cognitive impairment — whether due to AD or another cause — have higher risk to cause delirium and that can result in greater morbidity and mortality and a lasting increase in cognitive disability,” stated Dr. Pascual-Leone. Current recommendations emphasize exercise and fall prevention strategies to reduce fracture risk in patients with AD, but there is a lack of comprehensive research on the safety and efficacy of osteoporosis medications in this population.
 

Implications for Clinical Practice

The intricate interplay between AD and its comorbidities highlights the need for a comprehensive and integrated approach to patient care. The overlapping pathophysiologic mechanisms suggest that these comorbidities can contribute to the evolution and progression of AD. Likewise, AD can exacerbate comorbid conditions. As such, a holistic assessment strategy that prioritizes early detection and management of comorbid conditions to mitigate their impact on AD progression would be beneficial. Dr. Pascual-Leone added, “The presence of any of these comorbidities suggests a need to screen for MCI earlier than might otherwise be indicated or as part of the treatment for the comorbid condition. In many cases, patients can make lifestyle modifications that improve not only the comorbid condition but also reduce its effect on dementia.” In doing so, healthcare providers can help improve patient outcomes and enhance the overall quality of life for individuals living with AD.

Alissa Hershberger, Professor of Nursing, University of Central Missouri, Lee’s Summit, Missouri, has disclosed no relevant financial relationships.

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

Alzheimer’s disease (AD), the most common cause of dementia, is the fifth leading cause of death in the United States. An estimated 6.9 million Americans aged 65 years or older have AD. Comorbid conditions in AD may exacerbate the progression of dementia and negatively affect overall health.

Although the exact mechanisms remain unclear, systemic inflammation is thought to play a significant role in the development of many common comorbidities associated with AD. Among the most frequently observed comorbid conditions are hypertension, diabetes, and depression. The presence of these comorbidities affects the treatment and management of AD, underscoring the need to understand the mechanisms of their interrelationship and develop effective management strategies. 
 

Hypertension 

Hypertension is a well-established risk factor for numerous health conditions, including AD. A comprehensive review of five meta-analyses and 52 primary studies revealed that elevated systolic blood pressure (SBP) correlates with an 11 % increased risk of developing AD, raising the question of whether early intervention and control of blood pressure would mitigate the risk for AD later in life. 

Findings from the Northern Manhattan Study suggest that although elevated SBP contributes to cognitive decline in older patients, the use of antihypertensive medications can neutralize the effects of high SBP on certain cognitive functions. Furthermore, a systematic review and meta-analysis comprising 12 trials (92,135 participants) demonstrated a significant reduction in the risk for dementia and cognitive impairment with antihypertensive treatment.

Notably, a retrospective cohort study involving 69,081 participants treated with beta-blockers for hypertension found that beta-blockers with high blood-brain barrier permeability were associated with a reduced risk for AD compared with those with low blood-brain barrier permeability. Additionally, a secondary analysis of the SPRINT trial found antihypertensive medications that stimulate vs inhibit type 2 and 4 angiotensin II receptors were associated with a lower incidence of cognitive impairment. Although further clinical trials are necessary to directly assess specific medications, these findings emphasize the potential of antihypertensive treatment as a strategic approach to reduce the risk for AD.
 

Type 2 Diabetes 

The connection between AD and type 2 diabetes is such that AD is sometimes referred to as “type 3 diabetes.” Both diseases share some of the same underlying pathophysiologic mechanisms, particularly the development of insulin resistance and oxidative stress. A prospective cohort study of 10,095 participants showed that diabetes was significantly associated with a higher risk of developing dementia; this risk is even greater in patients who develop diabetes at an earlier age.

In an interview with this news organization, Alvaro Pascual-Leone, MD, PhD, a professor of neurology at Harvard Medical School, Boston, said, “In addition to being a comorbidity factor, diabetes appears to be a predisposing risk factor for AD.” This is supported by a comprehensive literature review showing an increased progression from mild cognitive impairment (MCI) to dementia in patients with diabetes, prediabetes, or metabolic syndrome, with a pooled odds ratio for dementia progression in individuals with diabetes of 1.53.

Owing to the overlapping pathophysiologic mechanisms in AD and diabetes, treating one condition may have beneficial effects on the other. A systematic umbrella review and meta-analysis that included 10 meta-analyses across nine classes of diabetes drugs found a protective effect against dementia with the use of metformin, thiazolidinediones (including pioglitazone), glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors. Moreover, a cohort study of 12,220 patients who discontinued metformin early (ie, stopped using metformin without a prior history of abnormal kidney function) and 29,126 patients considered routine users found an increased risk for dementia in the early terminator group. Although further research is warranted, the concurrent treatment of AD and diabetes with antidiabetic agents holds considerable promise.
 

Depression and Anxiety

Anxiety and depression are significant risk factors for AD, and conversely, AD increases the likelihood of developing these psychiatric conditions. A systematic review of 14,760 studies showed dysthymia often emerges during the early stages of AD as an emotional response to cognitive decline. 

Data from the Australian Imaging Biomarkers and Lifestyle study showed a markedly elevated risk for AD and MCI among individuals with preexisting anxiety or depression. This study also found that age, sex, and marital status are important determinants, with men and single individuals with depression being particularly susceptible to developing AD. Conversely, a cohort study of 129,410 AD patients with AD, 390,088 patients with all-cause dementia, and 3,900,880 age-matched controls without a history of depression showed a cumulative incidence of depression of 13% in the AD group vs 3% in the control group, suggesting a heightened risk for depression following an AD diagnosis. 

These findings underscore the importance of targeted screening and assessment for patients with anxiety and depression who may be at risk for AD or those diagnosed with AD who are at risk for subsequent depression and anxiety. Although antidepressants are effective in treating depression in general, their efficacy in AD-related depression is of variable quality, probably owing to differing pathophysiologic mechanisms of the disease. Further research is necessary to explore both pharmacologic and nonpharmacologic interventions for treating depression in AD patients. Some studies have found that cognitive behavioral-therapy can be effective in improving depression in patients with AD.
 

Sleep Disorders

Research has shown a strong correlation between AD and sleep disorders, particularly obstructive sleep apnea, insomnia, and circadian rhythm disruptions. Additionally, studies suggest that insomnia and sleep deprivation contribute to increased amyloid beta production and tau pathology, hallmark features of AD. A scoping review of 70 studies proposed that this relationship is mediated by the glymphatic system (glial-dependent waste clearance pathway in the central nervous system), and that sleep deprivation disrupts its function, leading to protein accumulation and subsequent neurologic symptoms of AD. Another study showed that sleep deprivation triggers glial cell activation, initiating an inflammatory cascade that accelerates AD progression.

Given that the gold standard treatment for obstructive sleep apnea is continuous positive airway pressure (CPAP), it has been hypothesized that CPAP could also alleviate AD symptoms owing to shared pathophysiologic mechanisms of these conditions. A large systemic review found that CPAP use improved AD symptoms in patients with mild AD or MCI, though other sleep interventions, such as cognitive-behavioral therapy and melatonin supplementation, have yielded mixed outcomes. However, most studies in this area are small in scale, and there remains a paucity of research on treating sleep disorders in AD patients, indicating a need for further investigation.
 

Musculoskeletal Disorders

Although no direct causative link has been established, research indicates an association between osteoarthritis (OA) and dementia, likely because of similar pathophysiologic mechanisms, including systemic inflammation. Longitudinal analyses of data from the Alzheimer’s Disease Neuroimaging Initiative study found cognitively normal older individuals with OA experience more rapid declines in hippocampal volumes compared to those without OA, suggesting that OA may elevate the risk of cognitive impairment. Current treatments for OA, such as nonsteroidal anti-inflammatory drugs, glucocorticoids, and disease-modifying OA drugs, might also help alleviate AD symptoms related to inflammation, though the research in this area is limited.

AD has also been linked to osteoporosis. In a longitudinal follow-up study involving 78,994 patients with osteoporosis and 78,994 controls, AD developed in 5856 patients with osteoporosis compared with 3761 patients in the control group. These findings represent a 1.27-fold higher incidence of AD in patients with osteoporosis than in the control group, suggesting that osteoporosis might be a risk factor for AD.

Additionally, research has identified a relationship between AD and increased fracture risk and decreased bone mineral density, with AD patients exhibiting a significantly higher likelihood of bone fractures compared with those without AD. “Falls and fractures, aside from the risk they pose in all geriatric patients, in individuals with cognitive impairment — whether due to AD or another cause — have higher risk to cause delirium and that can result in greater morbidity and mortality and a lasting increase in cognitive disability,” stated Dr. Pascual-Leone. Current recommendations emphasize exercise and fall prevention strategies to reduce fracture risk in patients with AD, but there is a lack of comprehensive research on the safety and efficacy of osteoporosis medications in this population.
 

Implications for Clinical Practice

The intricate interplay between AD and its comorbidities highlights the need for a comprehensive and integrated approach to patient care. The overlapping pathophysiologic mechanisms suggest that these comorbidities can contribute to the evolution and progression of AD. Likewise, AD can exacerbate comorbid conditions. As such, a holistic assessment strategy that prioritizes early detection and management of comorbid conditions to mitigate their impact on AD progression would be beneficial. Dr. Pascual-Leone added, “The presence of any of these comorbidities suggests a need to screen for MCI earlier than might otherwise be indicated or as part of the treatment for the comorbid condition. In many cases, patients can make lifestyle modifications that improve not only the comorbid condition but also reduce its effect on dementia.” In doing so, healthcare providers can help improve patient outcomes and enhance the overall quality of life for individuals living with AD.

Alissa Hershberger, Professor of Nursing, University of Central Missouri, Lee’s Summit, Missouri, has disclosed no relevant financial relationships.

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

Alzheimer’s disease (AD), the most common cause of dementia, is the fifth leading cause of death in the United States. An estimated 6.9 million Americans aged 65 years or older have AD. Comorbid conditions in AD may exacerbate the progression of dementia and negatively affect overall health.

Although the exact mechanisms remain unclear, systemic inflammation is thought to play a significant role in the development of many common comorbidities associated with AD. Among the most frequently observed comorbid conditions are hypertension, diabetes, and depression. The presence of these comorbidities affects the treatment and management of AD, underscoring the need to understand the mechanisms of their interrelationship and develop effective management strategies. 
 

Hypertension 

Hypertension is a well-established risk factor for numerous health conditions, including AD. A comprehensive review of five meta-analyses and 52 primary studies revealed that elevated systolic blood pressure (SBP) correlates with an 11 % increased risk of developing AD, raising the question of whether early intervention and control of blood pressure would mitigate the risk for AD later in life. 

Findings from the Northern Manhattan Study suggest that although elevated SBP contributes to cognitive decline in older patients, the use of antihypertensive medications can neutralize the effects of high SBP on certain cognitive functions. Furthermore, a systematic review and meta-analysis comprising 12 trials (92,135 participants) demonstrated a significant reduction in the risk for dementia and cognitive impairment with antihypertensive treatment.

Notably, a retrospective cohort study involving 69,081 participants treated with beta-blockers for hypertension found that beta-blockers with high blood-brain barrier permeability were associated with a reduced risk for AD compared with those with low blood-brain barrier permeability. Additionally, a secondary analysis of the SPRINT trial found antihypertensive medications that stimulate vs inhibit type 2 and 4 angiotensin II receptors were associated with a lower incidence of cognitive impairment. Although further clinical trials are necessary to directly assess specific medications, these findings emphasize the potential of antihypertensive treatment as a strategic approach to reduce the risk for AD.
 

Type 2 Diabetes 

The connection between AD and type 2 diabetes is such that AD is sometimes referred to as “type 3 diabetes.” Both diseases share some of the same underlying pathophysiologic mechanisms, particularly the development of insulin resistance and oxidative stress. A prospective cohort study of 10,095 participants showed that diabetes was significantly associated with a higher risk of developing dementia; this risk is even greater in patients who develop diabetes at an earlier age.

In an interview with this news organization, Alvaro Pascual-Leone, MD, PhD, a professor of neurology at Harvard Medical School, Boston, said, “In addition to being a comorbidity factor, diabetes appears to be a predisposing risk factor for AD.” This is supported by a comprehensive literature review showing an increased progression from mild cognitive impairment (MCI) to dementia in patients with diabetes, prediabetes, or metabolic syndrome, with a pooled odds ratio for dementia progression in individuals with diabetes of 1.53.

Owing to the overlapping pathophysiologic mechanisms in AD and diabetes, treating one condition may have beneficial effects on the other. A systematic umbrella review and meta-analysis that included 10 meta-analyses across nine classes of diabetes drugs found a protective effect against dementia with the use of metformin, thiazolidinediones (including pioglitazone), glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors. Moreover, a cohort study of 12,220 patients who discontinued metformin early (ie, stopped using metformin without a prior history of abnormal kidney function) and 29,126 patients considered routine users found an increased risk for dementia in the early terminator group. Although further research is warranted, the concurrent treatment of AD and diabetes with antidiabetic agents holds considerable promise.
 

Depression and Anxiety

Anxiety and depression are significant risk factors for AD, and conversely, AD increases the likelihood of developing these psychiatric conditions. A systematic review of 14,760 studies showed dysthymia often emerges during the early stages of AD as an emotional response to cognitive decline. 

Data from the Australian Imaging Biomarkers and Lifestyle study showed a markedly elevated risk for AD and MCI among individuals with preexisting anxiety or depression. This study also found that age, sex, and marital status are important determinants, with men and single individuals with depression being particularly susceptible to developing AD. Conversely, a cohort study of 129,410 AD patients with AD, 390,088 patients with all-cause dementia, and 3,900,880 age-matched controls without a history of depression showed a cumulative incidence of depression of 13% in the AD group vs 3% in the control group, suggesting a heightened risk for depression following an AD diagnosis. 

These findings underscore the importance of targeted screening and assessment for patients with anxiety and depression who may be at risk for AD or those diagnosed with AD who are at risk for subsequent depression and anxiety. Although antidepressants are effective in treating depression in general, their efficacy in AD-related depression is of variable quality, probably owing to differing pathophysiologic mechanisms of the disease. Further research is necessary to explore both pharmacologic and nonpharmacologic interventions for treating depression in AD patients. Some studies have found that cognitive behavioral-therapy can be effective in improving depression in patients with AD.
 

Sleep Disorders

Research has shown a strong correlation between AD and sleep disorders, particularly obstructive sleep apnea, insomnia, and circadian rhythm disruptions. Additionally, studies suggest that insomnia and sleep deprivation contribute to increased amyloid beta production and tau pathology, hallmark features of AD. A scoping review of 70 studies proposed that this relationship is mediated by the glymphatic system (glial-dependent waste clearance pathway in the central nervous system), and that sleep deprivation disrupts its function, leading to protein accumulation and subsequent neurologic symptoms of AD. Another study showed that sleep deprivation triggers glial cell activation, initiating an inflammatory cascade that accelerates AD progression.

Given that the gold standard treatment for obstructive sleep apnea is continuous positive airway pressure (CPAP), it has been hypothesized that CPAP could also alleviate AD symptoms owing to shared pathophysiologic mechanisms of these conditions. A large systemic review found that CPAP use improved AD symptoms in patients with mild AD or MCI, though other sleep interventions, such as cognitive-behavioral therapy and melatonin supplementation, have yielded mixed outcomes. However, most studies in this area are small in scale, and there remains a paucity of research on treating sleep disorders in AD patients, indicating a need for further investigation.
 

Musculoskeletal Disorders

Although no direct causative link has been established, research indicates an association between osteoarthritis (OA) and dementia, likely because of similar pathophysiologic mechanisms, including systemic inflammation. Longitudinal analyses of data from the Alzheimer’s Disease Neuroimaging Initiative study found cognitively normal older individuals with OA experience more rapid declines in hippocampal volumes compared to those without OA, suggesting that OA may elevate the risk of cognitive impairment. Current treatments for OA, such as nonsteroidal anti-inflammatory drugs, glucocorticoids, and disease-modifying OA drugs, might also help alleviate AD symptoms related to inflammation, though the research in this area is limited.

AD has also been linked to osteoporosis. In a longitudinal follow-up study involving 78,994 patients with osteoporosis and 78,994 controls, AD developed in 5856 patients with osteoporosis compared with 3761 patients in the control group. These findings represent a 1.27-fold higher incidence of AD in patients with osteoporosis than in the control group, suggesting that osteoporosis might be a risk factor for AD.

Additionally, research has identified a relationship between AD and increased fracture risk and decreased bone mineral density, with AD patients exhibiting a significantly higher likelihood of bone fractures compared with those without AD. “Falls and fractures, aside from the risk they pose in all geriatric patients, in individuals with cognitive impairment — whether due to AD or another cause — have higher risk to cause delirium and that can result in greater morbidity and mortality and a lasting increase in cognitive disability,” stated Dr. Pascual-Leone. Current recommendations emphasize exercise and fall prevention strategies to reduce fracture risk in patients with AD, but there is a lack of comprehensive research on the safety and efficacy of osteoporosis medications in this population.
 

Implications for Clinical Practice

The intricate interplay between AD and its comorbidities highlights the need for a comprehensive and integrated approach to patient care. The overlapping pathophysiologic mechanisms suggest that these comorbidities can contribute to the evolution and progression of AD. Likewise, AD can exacerbate comorbid conditions. As such, a holistic assessment strategy that prioritizes early detection and management of comorbid conditions to mitigate their impact on AD progression would be beneficial. Dr. Pascual-Leone added, “The presence of any of these comorbidities suggests a need to screen for MCI earlier than might otherwise be indicated or as part of the treatment for the comorbid condition. In many cases, patients can make lifestyle modifications that improve not only the comorbid condition but also reduce its effect on dementia.” In doing so, healthcare providers can help improve patient outcomes and enhance the overall quality of life for individuals living with AD.

Alissa Hershberger, Professor of Nursing, University of Central Missouri, Lee’s Summit, Missouri, has disclosed no relevant financial relationships.

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

There’s a new morning ritual in Pinedale, Wyoming, a town of about 2000, nestled against the Wind River Mountains.

Friends and neighbors in the oil- and gas-rich community “take their morning coffee and pull up” to watch workers building the county’s first hospital, said Kari DeWitt, the project’s public relations director.

“I think it’s just gratitude,” Ms. DeWitt said.

Sublette County is the only one in Wyoming — where counties span thousands of square miles — without a hospital. The 10-bed, 40,000-square-foot hospital, with a similarly sized attached long-term care facility, is slated to open by the summer of 2025.

Ms. DeWitt, who also is executive director of the Sublette County Health Foundation, has an office at the town’s health clinic with a window view of the construction.

Pinedale’s residents have good reason to be excited. New full-service hospitals with inpatient beds are rare in rural America, where declining population has spurred decades of downsizing and closures. Yet, a few communities in Wyoming and others in Kansas and Georgia are defying the trend.

“To be honest with you, it even seems strange to me,” said Wyoming Hospital Association President Eric Boley. Small rural “hospitals are really struggling all across the country,” he said.

There is no official tally of new hospitals being built in rural America, but industry experts such as Mr. Boley said they’re rare. Typically, health-related construction projects in rural areas are for smaller urgent care centers or stand-alone emergency facilities or are replacements for old hospitals.

About half of rural hospitals lost money in the prior year, according to Chartis, a health analytics and consulting firm. And nearly 150 rural hospitals have closed or converted to smaller operations since 2010, according to data collected by the University of North Carolina’s Cecil G. Sheps Center for Health Services Research.

To stem the tide of closures, Congress created a new rural emergency hospital designation that allowed struggling hospitals to close their inpatient units and provide only outpatient and emergency services. Since January 2023, when the program took effect, 32 of the more than 1700 eligible rural hospitals — from Georgia to New Mexico — have joined the program, according to data from the Centers for Medicare & Medicaid Services.

Tony Breitlow is healthcare studio director for EUA, which has extensive experience working for rural health care systems. Mr. Breitlow said his national architecture and engineering firm’s work expands, replaces, or revamps older buildings, many of which were constructed during the middle of the last century.

The work, Mr. Breitlow said, is part of health care “systems figuring out how to remain robust and viable.”

Freeman Health System, based in Joplin, Missouri, announced plans last year to build a new 50-bed hospital across the state line in Kansas. Paula Baker, Freeman’s president and chief executive, said the system is building for patients in the southeastern corner of the state who travel 45 minutes or more to its bigger Joplin facilities for care.

Freeman’s new hospital, with construction on the building expected to begin in the spring, will be less than 10 miles away from an older, 64-bed hospital that has existed for decades. Kansas is one of more than a dozen states with no “certificate of need” law that would require health providers to obtain approval from the state before offering new services or building or expanding facilities.

Ms. Baker also said Freeman plans to operate emergency services and a small 10-bed outpost in Fort Scott, Kansas, opening early next year in a corner of a hospital that closed in late 2018. Residents there “cried, they cheered, they hugged me,” Ms. Baker said, adding that the “level of appreciation and gratitude that they felt and they displayed was overwhelming to me.”

Michael Topchik, executive director of the Chartis Center for Rural Health, said regional healthcare systems in the Upper Midwest have been particularly active in competing for patients by, among other things, building new hospitals.

And while private corporate money can drive construction, many rural hospital projects tap government programs, especially those supported by the US Department of Agriculture, Mr. Topchik said. That, he said, “surprises a lot of people.”

Since 2021, the USDA’s rural Community Facilities Programs have awarded $2.24 billion in loans and grants to 68 rural hospitals for work that was not related to an emergency or disaster, according to data analyzed by KFF Health News and confirmed by the agency. The federal program is funded through what is often known as the farm bill, which faces a September congressional renewal deadline.

Nearly all the projects are replacements or expansions and updates of older facilities.

The USDA confirmed that three new or planned Wyoming hospitals received federal funding. Hospital projects in Riverton and Saratoga received loans of $37.2 million and $18.3 million, respectively. Pinedale’s hospital received a $29.2 million loan from the agency.

Wyoming’s new construction is rare in a state where more than 80% of rural hospitals reported losses in the third quarter of 2023, according to Chartis. The state association’s Mr. Boley said he worries about several hospitals that have less than 10 days’ cash on hand “day and night.”

Pinedale’s project loan was approved after the community submitted a feasibility study to the USDA that included local clinics and a long-term care facility. “It’s pretty remote and right up in the mountains,” Mr. Boley said.

Pinedale’s Ms. DeWitt said the community was missing key services, such as blood transfusions, which are often necessary when there is a trauma like a car crash or if a pregnant woman faces severe complications. Local ambulances drove 94,000 miles last year, she said.

Ms. DeWitt began working to raise support for the new hospital after her own pregnancy-related trauma in 2014. She was bleeding heavily and arrived at the local health clinic believing it operated like a hospital.

“It was shocking to hear, ‘No, we’re not a hospital. We can’t do blood transfusions. We’re just going to have to pray you live for the next 45 minutes,’ ” Ms. DeWitt said.

Ms. DeWitt had to be airlifted to Idaho, where she delivered a few minutes after landing. When the hospital financing went on the ballot in 2020, Ms. DeWitt — fully recovered, with healthy grade-schoolers at home — began making five calls a night to rally support for a county tax increase to help fund the hospital.

“By improving health care, I think we improve everybody’s chances of survival. You know, it’s pretty basic,” Ms. DeWitt said.

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about KFF.

There’s a new morning ritual in Pinedale, Wyoming, a town of about 2000, nestled against the Wind River Mountains.

Friends and neighbors in the oil- and gas-rich community “take their morning coffee and pull up” to watch workers building the county’s first hospital, said Kari DeWitt, the project’s public relations director.

“I think it’s just gratitude,” Ms. DeWitt said.

Sublette County is the only one in Wyoming — where counties span thousands of square miles — without a hospital. The 10-bed, 40,000-square-foot hospital, with a similarly sized attached long-term care facility, is slated to open by the summer of 2025.

Ms. DeWitt, who also is executive director of the Sublette County Health Foundation, has an office at the town’s health clinic with a window view of the construction.

Pinedale’s residents have good reason to be excited. New full-service hospitals with inpatient beds are rare in rural America, where declining population has spurred decades of downsizing and closures. Yet, a few communities in Wyoming and others in Kansas and Georgia are defying the trend.

“To be honest with you, it even seems strange to me,” said Wyoming Hospital Association President Eric Boley. Small rural “hospitals are really struggling all across the country,” he said.

There is no official tally of new hospitals being built in rural America, but industry experts such as Mr. Boley said they’re rare. Typically, health-related construction projects in rural areas are for smaller urgent care centers or stand-alone emergency facilities or are replacements for old hospitals.

About half of rural hospitals lost money in the prior year, according to Chartis, a health analytics and consulting firm. And nearly 150 rural hospitals have closed or converted to smaller operations since 2010, according to data collected by the University of North Carolina’s Cecil G. Sheps Center for Health Services Research.

To stem the tide of closures, Congress created a new rural emergency hospital designation that allowed struggling hospitals to close their inpatient units and provide only outpatient and emergency services. Since January 2023, when the program took effect, 32 of the more than 1700 eligible rural hospitals — from Georgia to New Mexico — have joined the program, according to data from the Centers for Medicare & Medicaid Services.

Tony Breitlow is healthcare studio director for EUA, which has extensive experience working for rural health care systems. Mr. Breitlow said his national architecture and engineering firm’s work expands, replaces, or revamps older buildings, many of which were constructed during the middle of the last century.

The work, Mr. Breitlow said, is part of health care “systems figuring out how to remain robust and viable.”

Freeman Health System, based in Joplin, Missouri, announced plans last year to build a new 50-bed hospital across the state line in Kansas. Paula Baker, Freeman’s president and chief executive, said the system is building for patients in the southeastern corner of the state who travel 45 minutes or more to its bigger Joplin facilities for care.

Freeman’s new hospital, with construction on the building expected to begin in the spring, will be less than 10 miles away from an older, 64-bed hospital that has existed for decades. Kansas is one of more than a dozen states with no “certificate of need” law that would require health providers to obtain approval from the state before offering new services or building or expanding facilities.

Ms. Baker also said Freeman plans to operate emergency services and a small 10-bed outpost in Fort Scott, Kansas, opening early next year in a corner of a hospital that closed in late 2018. Residents there “cried, they cheered, they hugged me,” Ms. Baker said, adding that the “level of appreciation and gratitude that they felt and they displayed was overwhelming to me.”

Michael Topchik, executive director of the Chartis Center for Rural Health, said regional healthcare systems in the Upper Midwest have been particularly active in competing for patients by, among other things, building new hospitals.

And while private corporate money can drive construction, many rural hospital projects tap government programs, especially those supported by the US Department of Agriculture, Mr. Topchik said. That, he said, “surprises a lot of people.”

Since 2021, the USDA’s rural Community Facilities Programs have awarded $2.24 billion in loans and grants to 68 rural hospitals for work that was not related to an emergency or disaster, according to data analyzed by KFF Health News and confirmed by the agency. The federal program is funded through what is often known as the farm bill, which faces a September congressional renewal deadline.

Nearly all the projects are replacements or expansions and updates of older facilities.

The USDA confirmed that three new or planned Wyoming hospitals received federal funding. Hospital projects in Riverton and Saratoga received loans of $37.2 million and $18.3 million, respectively. Pinedale’s hospital received a $29.2 million loan from the agency.

Wyoming’s new construction is rare in a state where more than 80% of rural hospitals reported losses in the third quarter of 2023, according to Chartis. The state association’s Mr. Boley said he worries about several hospitals that have less than 10 days’ cash on hand “day and night.”

Pinedale’s project loan was approved after the community submitted a feasibility study to the USDA that included local clinics and a long-term care facility. “It’s pretty remote and right up in the mountains,” Mr. Boley said.

Pinedale’s Ms. DeWitt said the community was missing key services, such as blood transfusions, which are often necessary when there is a trauma like a car crash or if a pregnant woman faces severe complications. Local ambulances drove 94,000 miles last year, she said.

Ms. DeWitt began working to raise support for the new hospital after her own pregnancy-related trauma in 2014. She was bleeding heavily and arrived at the local health clinic believing it operated like a hospital.

“It was shocking to hear, ‘No, we’re not a hospital. We can’t do blood transfusions. We’re just going to have to pray you live for the next 45 minutes,’ ” Ms. DeWitt said.

Ms. DeWitt had to be airlifted to Idaho, where she delivered a few minutes after landing. When the hospital financing went on the ballot in 2020, Ms. DeWitt — fully recovered, with healthy grade-schoolers at home — began making five calls a night to rally support for a county tax increase to help fund the hospital.

“By improving health care, I think we improve everybody’s chances of survival. You know, it’s pretty basic,” Ms. DeWitt said.

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about KFF.

There’s a new morning ritual in Pinedale, Wyoming, a town of about 2000, nestled against the Wind River Mountains.

Friends and neighbors in the oil- and gas-rich community “take their morning coffee and pull up” to watch workers building the county’s first hospital, said Kari DeWitt, the project’s public relations director.

“I think it’s just gratitude,” Ms. DeWitt said.

Sublette County is the only one in Wyoming — where counties span thousands of square miles — without a hospital. The 10-bed, 40,000-square-foot hospital, with a similarly sized attached long-term care facility, is slated to open by the summer of 2025.

Ms. DeWitt, who also is executive director of the Sublette County Health Foundation, has an office at the town’s health clinic with a window view of the construction.

Pinedale’s residents have good reason to be excited. New full-service hospitals with inpatient beds are rare in rural America, where declining population has spurred decades of downsizing and closures. Yet, a few communities in Wyoming and others in Kansas and Georgia are defying the trend.

“To be honest with you, it even seems strange to me,” said Wyoming Hospital Association President Eric Boley. Small rural “hospitals are really struggling all across the country,” he said.

There is no official tally of new hospitals being built in rural America, but industry experts such as Mr. Boley said they’re rare. Typically, health-related construction projects in rural areas are for smaller urgent care centers or stand-alone emergency facilities or are replacements for old hospitals.

About half of rural hospitals lost money in the prior year, according to Chartis, a health analytics and consulting firm. And nearly 150 rural hospitals have closed or converted to smaller operations since 2010, according to data collected by the University of North Carolina’s Cecil G. Sheps Center for Health Services Research.

To stem the tide of closures, Congress created a new rural emergency hospital designation that allowed struggling hospitals to close their inpatient units and provide only outpatient and emergency services. Since January 2023, when the program took effect, 32 of the more than 1700 eligible rural hospitals — from Georgia to New Mexico — have joined the program, according to data from the Centers for Medicare & Medicaid Services.

Tony Breitlow is healthcare studio director for EUA, which has extensive experience working for rural health care systems. Mr. Breitlow said his national architecture and engineering firm’s work expands, replaces, or revamps older buildings, many of which were constructed during the middle of the last century.

The work, Mr. Breitlow said, is part of health care “systems figuring out how to remain robust and viable.”

Freeman Health System, based in Joplin, Missouri, announced plans last year to build a new 50-bed hospital across the state line in Kansas. Paula Baker, Freeman’s president and chief executive, said the system is building for patients in the southeastern corner of the state who travel 45 minutes or more to its bigger Joplin facilities for care.

Freeman’s new hospital, with construction on the building expected to begin in the spring, will be less than 10 miles away from an older, 64-bed hospital that has existed for decades. Kansas is one of more than a dozen states with no “certificate of need” law that would require health providers to obtain approval from the state before offering new services or building or expanding facilities.

Ms. Baker also said Freeman plans to operate emergency services and a small 10-bed outpost in Fort Scott, Kansas, opening early next year in a corner of a hospital that closed in late 2018. Residents there “cried, they cheered, they hugged me,” Ms. Baker said, adding that the “level of appreciation and gratitude that they felt and they displayed was overwhelming to me.”

Michael Topchik, executive director of the Chartis Center for Rural Health, said regional healthcare systems in the Upper Midwest have been particularly active in competing for patients by, among other things, building new hospitals.

And while private corporate money can drive construction, many rural hospital projects tap government programs, especially those supported by the US Department of Agriculture, Mr. Topchik said. That, he said, “surprises a lot of people.”

Since 2021, the USDA’s rural Community Facilities Programs have awarded $2.24 billion in loans and grants to 68 rural hospitals for work that was not related to an emergency or disaster, according to data analyzed by KFF Health News and confirmed by the agency. The federal program is funded through what is often known as the farm bill, which faces a September congressional renewal deadline.

Nearly all the projects are replacements or expansions and updates of older facilities.

The USDA confirmed that three new or planned Wyoming hospitals received federal funding. Hospital projects in Riverton and Saratoga received loans of $37.2 million and $18.3 million, respectively. Pinedale’s hospital received a $29.2 million loan from the agency.

Wyoming’s new construction is rare in a state where more than 80% of rural hospitals reported losses in the third quarter of 2023, according to Chartis. The state association’s Mr. Boley said he worries about several hospitals that have less than 10 days’ cash on hand “day and night.”

Pinedale’s project loan was approved after the community submitted a feasibility study to the USDA that included local clinics and a long-term care facility. “It’s pretty remote and right up in the mountains,” Mr. Boley said.

Pinedale’s Ms. DeWitt said the community was missing key services, such as blood transfusions, which are often necessary when there is a trauma like a car crash or if a pregnant woman faces severe complications. Local ambulances drove 94,000 miles last year, she said.

Ms. DeWitt began working to raise support for the new hospital after her own pregnancy-related trauma in 2014. She was bleeding heavily and arrived at the local health clinic believing it operated like a hospital.

“It was shocking to hear, ‘No, we’re not a hospital. We can’t do blood transfusions. We’re just going to have to pray you live for the next 45 minutes,’ ” Ms. DeWitt said.

Ms. DeWitt had to be airlifted to Idaho, where she delivered a few minutes after landing. When the hospital financing went on the ballot in 2020, Ms. DeWitt — fully recovered, with healthy grade-schoolers at home — began making five calls a night to rally support for a county tax increase to help fund the hospital.

“By improving health care, I think we improve everybody’s chances of survival. You know, it’s pretty basic,” Ms. DeWitt said.

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about KFF.

COPENHAGEN — Women of childbearing age with multiple sclerosis (MS) receive fewer highly effective medications than do men with similar levels of disability, even after accounting for treatment discontinuations during pregnancy and the postpartum period, new research suggested.

“We believe that pregnancy-related considerations probably still explain the major part of this gap,” said Antoine Gavoille, MD, University of Lyon, France, who presented the study at the 2024 ECTRIMS annual meeting.

This is likely due to “factors such as anticipation of pregnancy long before it occurs and fear of exposing women of childbearing age to certain treatments even in the absence of planned pregnancy,” he added.

Caution is warranted when medications are first marketed because there are no data on safety in pregnancy. However, in 2024, “this lesser treatment in women is unacceptable,” said Dr. Gavoille. “We now have several highly effective treatment options which are compatible with pregnancy,” he noted.

The researchers analyzed the French MS registry of 22,657 patients with relapsing MS (74.2% women) between 1997 and 2022 for treatment differences between women and their male counterparts. The results were adjusted for multiple factors including educational level, disease activity, disability levels, and discontinuation of drugs during pregnancy.

They found that over a median follow-up of 11.6 years, women had a significantly lower probability of receiving any disease-modifying treatment (odds ratio [OR], 0.92; 95% CI, 0.87-0.97).

In addition, women were even less likely to receive high-efficacy treatments such as natalizumab, anti-CD20 antibodies, or S1P modulators such as fingolimod (OR, 0.80; 95% CI, 0.74-0.86).

The difference in disease-modifying treatment usage varied across different treatments and over time. Teriflunomide, fingolimod, and anti-CD20 therapies were significantly underused throughout their entire availability (OR, 0.87, 0.78, and 0.80, respectively).

Interferon and natalizumab were initially used less frequently in women, but the use of these medications equalized over time.

In contrast, glatiramer acetate and dimethyl fumarate were initially used equally between genders but eventually became more commonly prescribed to women (OR, 1.27 and 1.17, respectively).

The disparity in treatment emerged after 2 years of disease duration for disease-modifying treatments in general and as early as 1 year for highly effective treatments.

The gender-based treatment gap did not significantly vary with patient age, indicating that therapeutic inertia may persist regardless of a woman’s age.

“Women may not be receiving the most effective therapies at the optimal time, often due to concerns about pregnancy risks that may never materialize,” said the study’s lead investigator Sandra Vukusic, MD, Lyon University Hospital, France.

“The main impact of this therapeutic inertia in women is the less effective control of disease activity, leading to the accumulation of lesions and an increased risk of long-term disability. This represents a real loss of opportunity for women, especially in an era where disease-modifying treatments so effective when used early,” she added.

Dr. Gavoille said that recommendations in France allow the use of moderately active drugs, including interferon and glatiramer acetate, during pregnancy or in women planning a pregnancy. More recently there has been enough data to allow the use of natalizumab up until the second trimester.

In addition, although not in the guidelines, it is thought that the anti-CD20 monoclonal antibodies, such as rituximab or ocrelizumab, may be safe as they are very long acting. Women can be dosed before pregnancy and be covered for the whole pregnancy period without exposing the fetus to the drug, he explained.

“The message is that now we have both moderately and highly effective treatments that are compatible with a pregnancy plan,” Dr. Gavoille said.

First, clinicians have to select a level of treatment based on disease activity and then choose the best option, depending on the woman’s plans with respect to pregnancy.

Drugs that are contraindicated in pregnancy include teriflunomide and S1P modulators such as fingolimod, which have been shown to be harmful to the fetus.

“But they could still be used in women of childbearing years as long as they are not planning a pregnancy and understand the need for contraception,” Dr. Gavoille noted.

He believes both neurologists and patients are afraid of using drugs in pregnancy. “It is, of course, important to be cautious on this issue, but we should not let fear stop these women receiving the best treatments available.”

However, he added, clinical practice is changing, and confidence is gradually building around using highly effective treatments in women of childbearing age.

Dr. Gavoille also called for more research to collate data in pregnant women with MS who are exposed to various treatments, starting with case reports and then academic registries, which he described as “difficult but important work.”

Commenting on the study, Robert Hoepner, MD, University Hospital of Bern, Switzerland, agreed that this treatment disparity between men and women is “unacceptable.”

Dr. Hoepner noted that a recent study showed that women have different relapse symptoms than men, which may also affect treatment choice.

Dr. Gavoille responded that other research has shown that women are less likely to have treatment escalation post-relapse. “This could be because of a difference in symptoms. But this is something we haven’t looked at yet.” 

Also commenting on the research, Frauke Zipp, MD, University Medical Center Mainz in Germany, said it would be interesting to follow this cohort over the long term to see if the women do less well several years down the line.

The study authors and commentators reported no relevant disclosures.
 

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

COPENHAGEN — Women of childbearing age with multiple sclerosis (MS) receive fewer highly effective medications than do men with similar levels of disability, even after accounting for treatment discontinuations during pregnancy and the postpartum period, new research suggested.

“We believe that pregnancy-related considerations probably still explain the major part of this gap,” said Antoine Gavoille, MD, University of Lyon, France, who presented the study at the 2024 ECTRIMS annual meeting.

This is likely due to “factors such as anticipation of pregnancy long before it occurs and fear of exposing women of childbearing age to certain treatments even in the absence of planned pregnancy,” he added.

Caution is warranted when medications are first marketed because there are no data on safety in pregnancy. However, in 2024, “this lesser treatment in women is unacceptable,” said Dr. Gavoille. “We now have several highly effective treatment options which are compatible with pregnancy,” he noted.

The researchers analyzed the French MS registry of 22,657 patients with relapsing MS (74.2% women) between 1997 and 2022 for treatment differences between women and their male counterparts. The results were adjusted for multiple factors including educational level, disease activity, disability levels, and discontinuation of drugs during pregnancy.

They found that over a median follow-up of 11.6 years, women had a significantly lower probability of receiving any disease-modifying treatment (odds ratio [OR], 0.92; 95% CI, 0.87-0.97).

In addition, women were even less likely to receive high-efficacy treatments such as natalizumab, anti-CD20 antibodies, or S1P modulators such as fingolimod (OR, 0.80; 95% CI, 0.74-0.86).

The difference in disease-modifying treatment usage varied across different treatments and over time. Teriflunomide, fingolimod, and anti-CD20 therapies were significantly underused throughout their entire availability (OR, 0.87, 0.78, and 0.80, respectively).

Interferon and natalizumab were initially used less frequently in women, but the use of these medications equalized over time.

In contrast, glatiramer acetate and dimethyl fumarate were initially used equally between genders but eventually became more commonly prescribed to women (OR, 1.27 and 1.17, respectively).

The disparity in treatment emerged after 2 years of disease duration for disease-modifying treatments in general and as early as 1 year for highly effective treatments.

The gender-based treatment gap did not significantly vary with patient age, indicating that therapeutic inertia may persist regardless of a woman’s age.

“Women may not be receiving the most effective therapies at the optimal time, often due to concerns about pregnancy risks that may never materialize,” said the study’s lead investigator Sandra Vukusic, MD, Lyon University Hospital, France.

“The main impact of this therapeutic inertia in women is the less effective control of disease activity, leading to the accumulation of lesions and an increased risk of long-term disability. This represents a real loss of opportunity for women, especially in an era where disease-modifying treatments so effective when used early,” she added.

Dr. Gavoille said that recommendations in France allow the use of moderately active drugs, including interferon and glatiramer acetate, during pregnancy or in women planning a pregnancy. More recently there has been enough data to allow the use of natalizumab up until the second trimester.

In addition, although not in the guidelines, it is thought that the anti-CD20 monoclonal antibodies, such as rituximab or ocrelizumab, may be safe as they are very long acting. Women can be dosed before pregnancy and be covered for the whole pregnancy period without exposing the fetus to the drug, he explained.

“The message is that now we have both moderately and highly effective treatments that are compatible with a pregnancy plan,” Dr. Gavoille said.

First, clinicians have to select a level of treatment based on disease activity and then choose the best option, depending on the woman’s plans with respect to pregnancy.

Drugs that are contraindicated in pregnancy include teriflunomide and S1P modulators such as fingolimod, which have been shown to be harmful to the fetus.

“But they could still be used in women of childbearing years as long as they are not planning a pregnancy and understand the need for contraception,” Dr. Gavoille noted.

He believes both neurologists and patients are afraid of using drugs in pregnancy. “It is, of course, important to be cautious on this issue, but we should not let fear stop these women receiving the best treatments available.”

However, he added, clinical practice is changing, and confidence is gradually building around using highly effective treatments in women of childbearing age.

Dr. Gavoille also called for more research to collate data in pregnant women with MS who are exposed to various treatments, starting with case reports and then academic registries, which he described as “difficult but important work.”

Commenting on the study, Robert Hoepner, MD, University Hospital of Bern, Switzerland, agreed that this treatment disparity between men and women is “unacceptable.”

Dr. Hoepner noted that a recent study showed that women have different relapse symptoms than men, which may also affect treatment choice.

Dr. Gavoille responded that other research has shown that women are less likely to have treatment escalation post-relapse. “This could be because of a difference in symptoms. But this is something we haven’t looked at yet.” 

Also commenting on the research, Frauke Zipp, MD, University Medical Center Mainz in Germany, said it would be interesting to follow this cohort over the long term to see if the women do less well several years down the line.

The study authors and commentators reported no relevant disclosures.
 

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

COPENHAGEN — Women of childbearing age with multiple sclerosis (MS) receive fewer highly effective medications than do men with similar levels of disability, even after accounting for treatment discontinuations during pregnancy and the postpartum period, new research suggested.

“We believe that pregnancy-related considerations probably still explain the major part of this gap,” said Antoine Gavoille, MD, University of Lyon, France, who presented the study at the 2024 ECTRIMS annual meeting.

This is likely due to “factors such as anticipation of pregnancy long before it occurs and fear of exposing women of childbearing age to certain treatments even in the absence of planned pregnancy,” he added.

Caution is warranted when medications are first marketed because there are no data on safety in pregnancy. However, in 2024, “this lesser treatment in women is unacceptable,” said Dr. Gavoille. “We now have several highly effective treatment options which are compatible with pregnancy,” he noted.

The researchers analyzed the French MS registry of 22,657 patients with relapsing MS (74.2% women) between 1997 and 2022 for treatment differences between women and their male counterparts. The results were adjusted for multiple factors including educational level, disease activity, disability levels, and discontinuation of drugs during pregnancy.

They found that over a median follow-up of 11.6 years, women had a significantly lower probability of receiving any disease-modifying treatment (odds ratio [OR], 0.92; 95% CI, 0.87-0.97).

In addition, women were even less likely to receive high-efficacy treatments such as natalizumab, anti-CD20 antibodies, or S1P modulators such as fingolimod (OR, 0.80; 95% CI, 0.74-0.86).

The difference in disease-modifying treatment usage varied across different treatments and over time. Teriflunomide, fingolimod, and anti-CD20 therapies were significantly underused throughout their entire availability (OR, 0.87, 0.78, and 0.80, respectively).

Interferon and natalizumab were initially used less frequently in women, but the use of these medications equalized over time.

In contrast, glatiramer acetate and dimethyl fumarate were initially used equally between genders but eventually became more commonly prescribed to women (OR, 1.27 and 1.17, respectively).

The disparity in treatment emerged after 2 years of disease duration for disease-modifying treatments in general and as early as 1 year for highly effective treatments.

The gender-based treatment gap did not significantly vary with patient age, indicating that therapeutic inertia may persist regardless of a woman’s age.

“Women may not be receiving the most effective therapies at the optimal time, often due to concerns about pregnancy risks that may never materialize,” said the study’s lead investigator Sandra Vukusic, MD, Lyon University Hospital, France.

“The main impact of this therapeutic inertia in women is the less effective control of disease activity, leading to the accumulation of lesions and an increased risk of long-term disability. This represents a real loss of opportunity for women, especially in an era where disease-modifying treatments so effective when used early,” she added.

Dr. Gavoille said that recommendations in France allow the use of moderately active drugs, including interferon and glatiramer acetate, during pregnancy or in women planning a pregnancy. More recently there has been enough data to allow the use of natalizumab up until the second trimester.

In addition, although not in the guidelines, it is thought that the anti-CD20 monoclonal antibodies, such as rituximab or ocrelizumab, may be safe as they are very long acting. Women can be dosed before pregnancy and be covered for the whole pregnancy period without exposing the fetus to the drug, he explained.

“The message is that now we have both moderately and highly effective treatments that are compatible with a pregnancy plan,” Dr. Gavoille said.

First, clinicians have to select a level of treatment based on disease activity and then choose the best option, depending on the woman’s plans with respect to pregnancy.

Drugs that are contraindicated in pregnancy include teriflunomide and S1P modulators such as fingolimod, which have been shown to be harmful to the fetus.

“But they could still be used in women of childbearing years as long as they are not planning a pregnancy and understand the need for contraception,” Dr. Gavoille noted.

He believes both neurologists and patients are afraid of using drugs in pregnancy. “It is, of course, important to be cautious on this issue, but we should not let fear stop these women receiving the best treatments available.”

However, he added, clinical practice is changing, and confidence is gradually building around using highly effective treatments in women of childbearing age.

Dr. Gavoille also called for more research to collate data in pregnant women with MS who are exposed to various treatments, starting with case reports and then academic registries, which he described as “difficult but important work.”

Commenting on the study, Robert Hoepner, MD, University Hospital of Bern, Switzerland, agreed that this treatment disparity between men and women is “unacceptable.”

Dr. Hoepner noted that a recent study showed that women have different relapse symptoms than men, which may also affect treatment choice.

Dr. Gavoille responded that other research has shown that women are less likely to have treatment escalation post-relapse. “This could be because of a difference in symptoms. But this is something we haven’t looked at yet.” 

Also commenting on the research, Frauke Zipp, MD, University Medical Center Mainz in Germany, said it would be interesting to follow this cohort over the long term to see if the women do less well several years down the line.

The study authors and commentators reported no relevant disclosures.
 

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

MILAN — Antidepressants escitalopram and duloxetine have been shown to improve verbal memory in moderate to severe depression, a clinical effect linked to changes in serotonin 4 (5-HT4) receptor levels in the brain, as shown on PET.

These findings suggested there is a role for specifically targeting the 5-HT4 receptor to improve verbal memory in depression, said investigator Vibeke H. Dam, PhD, from Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

“Verbal memory is often impaired in depression, and this has a lot of impact on patients’ ability to work and have a normal life. That’s why we’re so excited about this receptor in particular,” Dr. Dam said.

“If we can find a way to activate it more directly, we’re thinking this could be a way to treat this memory symptom that a lot of patients have and that currently we don’t really have a treatment for,” she added.

The findings were presented at the 37th European College of Neuropsychopharmacology (ECNP) Congress and recently published in Biological Psychiatry .
 

Largest Trial of Its Kind

The study is the largest single-site PET trial investigating serotonergic neurotransmission in major depressive disorder over the course of antidepressant treatment to date. It included 90 patients with moderate to severe depression who underwent baseline cognitive tests and brain scans to measure 5-HT4 receptor levels before starting their treatment with the selective serotonin reuptake inhibitor escitalopram.

Patients who showed no improvement in depressive symptoms after 4 weeks (n = 14), as assessed by the Hamilton Depression Rating Scale 6 (HAMD6), were switched to the serotonin-norepinephrine reuptake inhibitor duloxetine.

Both escitalopram and duloxetine inhibit the reuptake of 5-HT4, enhancing neurotransmitter activity; escitalopram primarily increases serotonin levels, while duloxetine increases both serotonin and norepinephrine levels.

The primary cognitive outcome measure was change in the Verbal Affective Memory Task 26. Secondary cognitive outcomes were change in working memory, reaction time, emotion recognition bias, and negative social emotion.

After 8 weeks of treatment, a subset of 40 patients repeated PET scans, and at 12 weeks, all patients repeated cognitive testing.

Matching neuroimaging and cognitive data were available for 88 patients at baseline and for 39 patients with rescan.

As expected, the study showed that antidepressant treatment resulted in the downregulation of 5-HT4 receptor levels. “One hypothesis is that if we increase the availability of serotonin [with treatment], downregulation of the receptors might be a response,” said Dr. Dam.

“What was interesting was that this was the effect across all patients, whether they [clinically] responded or not. So we see the medication does what it’s supposed to do in the brain.” But, she said, there was no association between 5-HT4 receptor levels and HAMD6 scores.
 

Gains in Verbal Memory

Although the downregulation of 5-HT4 did not correlate with somatic or mood symptoms, it did correlate with cognitive symptoms.

Interestingly, while most patients showed improvement in depressive symptoms — many reaching remission or recovery — they also experienced gains in verbal memory. However, these improvements were not correlated. It was possible for one to improve more than the other, with no apparent link between the two, said Dr. Dam.

“What was linked was how the brain responded to the medication for this particular receptor. So even though there is this downregulation of the receptor, there’s still a lot of activation of it, and our thinking is that it’s activation of the receptor that is the important bit.”

Work by other groups has shown that another medication, prucalopride, which is used to treat gastroparesis, can more directly activate the 5-HT4 receptor, and that the treatment of healthy volunteers with this medication can boost memory and learning, said Dr. Dam.

“We could repurpose this drug, and we’re currently looking for funding to test this in a wide variety of different groups such as concussion, diabetes, and depression.”

The study’s coinvestigator, Vibe G. Frokjaer, MD, said more research is required to understand the potential implications of the findings.

“Poor cognitive function is very hard to treat efficiently and may require extra treatment. This work points to the possibility of stimulating this specific receptor so that we can treat cognitive problems, even aside from whether or not the patient has overcome the core symptoms of depression,” she said in a release.

Commenting on the research, Philip Cowen, MD, professor of psychopharmacology at the University of Oxford, England, said in a release that in light of “recent controversies about the role of brain serotonin in clinical depression, it is noteworthy that the PET studies of the Copenhagen Group provide unequivocal evidence that brain 5-HT4 receptors are decreased in unmedicated depressed patients.

“Their work also demonstrates the intimate role of brain 5-HT4 receptors in cognitive function,” he added. “This confirms recent work from Oxford, showing that the 5-HT4 receptor stimulant, prucalopride — a drug licensed for the treatment of constipation — improves memory in both healthy participants and people at risk of depression,” he added.

The study was funded by the Innovation Fund Denmark, Research Fund of the Mental Health Services – Capital Region of Denmark, Independent Research Fund Denmark, Global Justice Foundation, Research Council of Rigshospitalet, Augustinus Foundation, Savværksejer Jeppe Juhl og hustru Ovita Juhls Mindelegat, Lundbeck Foundation, and H. Lundbeck A/S.

Dr. Dam reported serving as a speaker for H. Lundbeck. Frokjaer reported serving as a consultant for Sage Therapeutics and lecturer for H. Lundbeck, Janssen-Cilag, and Gedeon Richter. Study investigator Martin B. Jørgensen has given talks sponsored by Boehringer Ingelheim and Lundbeck Pharma. All other investigators reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

MILAN — Antidepressants escitalopram and duloxetine have been shown to improve verbal memory in moderate to severe depression, a clinical effect linked to changes in serotonin 4 (5-HT4) receptor levels in the brain, as shown on PET.

These findings suggested there is a role for specifically targeting the 5-HT4 receptor to improve verbal memory in depression, said investigator Vibeke H. Dam, PhD, from Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

“Verbal memory is often impaired in depression, and this has a lot of impact on patients’ ability to work and have a normal life. That’s why we’re so excited about this receptor in particular,” Dr. Dam said.

“If we can find a way to activate it more directly, we’re thinking this could be a way to treat this memory symptom that a lot of patients have and that currently we don’t really have a treatment for,” she added.

The findings were presented at the 37th European College of Neuropsychopharmacology (ECNP) Congress and recently published in Biological Psychiatry .
 

Largest Trial of Its Kind

The study is the largest single-site PET trial investigating serotonergic neurotransmission in major depressive disorder over the course of antidepressant treatment to date. It included 90 patients with moderate to severe depression who underwent baseline cognitive tests and brain scans to measure 5-HT4 receptor levels before starting their treatment with the selective serotonin reuptake inhibitor escitalopram.

Patients who showed no improvement in depressive symptoms after 4 weeks (n = 14), as assessed by the Hamilton Depression Rating Scale 6 (HAMD6), were switched to the serotonin-norepinephrine reuptake inhibitor duloxetine.

Both escitalopram and duloxetine inhibit the reuptake of 5-HT4, enhancing neurotransmitter activity; escitalopram primarily increases serotonin levels, while duloxetine increases both serotonin and norepinephrine levels.

The primary cognitive outcome measure was change in the Verbal Affective Memory Task 26. Secondary cognitive outcomes were change in working memory, reaction time, emotion recognition bias, and negative social emotion.

After 8 weeks of treatment, a subset of 40 patients repeated PET scans, and at 12 weeks, all patients repeated cognitive testing.

Matching neuroimaging and cognitive data were available for 88 patients at baseline and for 39 patients with rescan.

As expected, the study showed that antidepressant treatment resulted in the downregulation of 5-HT4 receptor levels. “One hypothesis is that if we increase the availability of serotonin [with treatment], downregulation of the receptors might be a response,” said Dr. Dam.

“What was interesting was that this was the effect across all patients, whether they [clinically] responded or not. So we see the medication does what it’s supposed to do in the brain.” But, she said, there was no association between 5-HT4 receptor levels and HAMD6 scores.
 

Gains in Verbal Memory

Although the downregulation of 5-HT4 did not correlate with somatic or mood symptoms, it did correlate with cognitive symptoms.

Interestingly, while most patients showed improvement in depressive symptoms — many reaching remission or recovery — they also experienced gains in verbal memory. However, these improvements were not correlated. It was possible for one to improve more than the other, with no apparent link between the two, said Dr. Dam.

“What was linked was how the brain responded to the medication for this particular receptor. So even though there is this downregulation of the receptor, there’s still a lot of activation of it, and our thinking is that it’s activation of the receptor that is the important bit.”

Work by other groups has shown that another medication, prucalopride, which is used to treat gastroparesis, can more directly activate the 5-HT4 receptor, and that the treatment of healthy volunteers with this medication can boost memory and learning, said Dr. Dam.

“We could repurpose this drug, and we’re currently looking for funding to test this in a wide variety of different groups such as concussion, diabetes, and depression.”

The study’s coinvestigator, Vibe G. Frokjaer, MD, said more research is required to understand the potential implications of the findings.

“Poor cognitive function is very hard to treat efficiently and may require extra treatment. This work points to the possibility of stimulating this specific receptor so that we can treat cognitive problems, even aside from whether or not the patient has overcome the core symptoms of depression,” she said in a release.

Commenting on the research, Philip Cowen, MD, professor of psychopharmacology at the University of Oxford, England, said in a release that in light of “recent controversies about the role of brain serotonin in clinical depression, it is noteworthy that the PET studies of the Copenhagen Group provide unequivocal evidence that brain 5-HT4 receptors are decreased in unmedicated depressed patients.

“Their work also demonstrates the intimate role of brain 5-HT4 receptors in cognitive function,” he added. “This confirms recent work from Oxford, showing that the 5-HT4 receptor stimulant, prucalopride — a drug licensed for the treatment of constipation — improves memory in both healthy participants and people at risk of depression,” he added.

The study was funded by the Innovation Fund Denmark, Research Fund of the Mental Health Services – Capital Region of Denmark, Independent Research Fund Denmark, Global Justice Foundation, Research Council of Rigshospitalet, Augustinus Foundation, Savværksejer Jeppe Juhl og hustru Ovita Juhls Mindelegat, Lundbeck Foundation, and H. Lundbeck A/S.

Dr. Dam reported serving as a speaker for H. Lundbeck. Frokjaer reported serving as a consultant for Sage Therapeutics and lecturer for H. Lundbeck, Janssen-Cilag, and Gedeon Richter. Study investigator Martin B. Jørgensen has given talks sponsored by Boehringer Ingelheim and Lundbeck Pharma. All other investigators reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

MILAN — Antidepressants escitalopram and duloxetine have been shown to improve verbal memory in moderate to severe depression, a clinical effect linked to changes in serotonin 4 (5-HT4) receptor levels in the brain, as shown on PET.

These findings suggested there is a role for specifically targeting the 5-HT4 receptor to improve verbal memory in depression, said investigator Vibeke H. Dam, PhD, from Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

“Verbal memory is often impaired in depression, and this has a lot of impact on patients’ ability to work and have a normal life. That’s why we’re so excited about this receptor in particular,” Dr. Dam said.

“If we can find a way to activate it more directly, we’re thinking this could be a way to treat this memory symptom that a lot of patients have and that currently we don’t really have a treatment for,” she added.

The findings were presented at the 37th European College of Neuropsychopharmacology (ECNP) Congress and recently published in Biological Psychiatry .
 

Largest Trial of Its Kind

The study is the largest single-site PET trial investigating serotonergic neurotransmission in major depressive disorder over the course of antidepressant treatment to date. It included 90 patients with moderate to severe depression who underwent baseline cognitive tests and brain scans to measure 5-HT4 receptor levels before starting their treatment with the selective serotonin reuptake inhibitor escitalopram.

Patients who showed no improvement in depressive symptoms after 4 weeks (n = 14), as assessed by the Hamilton Depression Rating Scale 6 (HAMD6), were switched to the serotonin-norepinephrine reuptake inhibitor duloxetine.

Both escitalopram and duloxetine inhibit the reuptake of 5-HT4, enhancing neurotransmitter activity; escitalopram primarily increases serotonin levels, while duloxetine increases both serotonin and norepinephrine levels.

The primary cognitive outcome measure was change in the Verbal Affective Memory Task 26. Secondary cognitive outcomes were change in working memory, reaction time, emotion recognition bias, and negative social emotion.

After 8 weeks of treatment, a subset of 40 patients repeated PET scans, and at 12 weeks, all patients repeated cognitive testing.

Matching neuroimaging and cognitive data were available for 88 patients at baseline and for 39 patients with rescan.

As expected, the study showed that antidepressant treatment resulted in the downregulation of 5-HT4 receptor levels. “One hypothesis is that if we increase the availability of serotonin [with treatment], downregulation of the receptors might be a response,” said Dr. Dam.

“What was interesting was that this was the effect across all patients, whether they [clinically] responded or not. So we see the medication does what it’s supposed to do in the brain.” But, she said, there was no association between 5-HT4 receptor levels and HAMD6 scores.
 

Gains in Verbal Memory

Although the downregulation of 5-HT4 did not correlate with somatic or mood symptoms, it did correlate with cognitive symptoms.

Interestingly, while most patients showed improvement in depressive symptoms — many reaching remission or recovery — they also experienced gains in verbal memory. However, these improvements were not correlated. It was possible for one to improve more than the other, with no apparent link between the two, said Dr. Dam.

“What was linked was how the brain responded to the medication for this particular receptor. So even though there is this downregulation of the receptor, there’s still a lot of activation of it, and our thinking is that it’s activation of the receptor that is the important bit.”

Work by other groups has shown that another medication, prucalopride, which is used to treat gastroparesis, can more directly activate the 5-HT4 receptor, and that the treatment of healthy volunteers with this medication can boost memory and learning, said Dr. Dam.

“We could repurpose this drug, and we’re currently looking for funding to test this in a wide variety of different groups such as concussion, diabetes, and depression.”

The study’s coinvestigator, Vibe G. Frokjaer, MD, said more research is required to understand the potential implications of the findings.

“Poor cognitive function is very hard to treat efficiently and may require extra treatment. This work points to the possibility of stimulating this specific receptor so that we can treat cognitive problems, even aside from whether or not the patient has overcome the core symptoms of depression,” she said in a release.

Commenting on the research, Philip Cowen, MD, professor of psychopharmacology at the University of Oxford, England, said in a release that in light of “recent controversies about the role of brain serotonin in clinical depression, it is noteworthy that the PET studies of the Copenhagen Group provide unequivocal evidence that brain 5-HT4 receptors are decreased in unmedicated depressed patients.

“Their work also demonstrates the intimate role of brain 5-HT4 receptors in cognitive function,” he added. “This confirms recent work from Oxford, showing that the 5-HT4 receptor stimulant, prucalopride — a drug licensed for the treatment of constipation — improves memory in both healthy participants and people at risk of depression,” he added.

The study was funded by the Innovation Fund Denmark, Research Fund of the Mental Health Services – Capital Region of Denmark, Independent Research Fund Denmark, Global Justice Foundation, Research Council of Rigshospitalet, Augustinus Foundation, Savværksejer Jeppe Juhl og hustru Ovita Juhls Mindelegat, Lundbeck Foundation, and H. Lundbeck A/S.

Dr. Dam reported serving as a speaker for H. Lundbeck. Frokjaer reported serving as a consultant for Sage Therapeutics and lecturer for H. Lundbeck, Janssen-Cilag, and Gedeon Richter. Study investigator Martin B. Jørgensen has given talks sponsored by Boehringer Ingelheim and Lundbeck Pharma. All other investigators reported no relevant disclosures.
 

A version of this article appeared on Medscape.com.

Demand for new weight loss drugs has surged over the past few years. 

Led by the antiobesity drugs semaglutide (Wegovy) and tirzepatide (Zepbound), these popular medications — more commonly known as glucagon-like peptide 1 (GLP-1) agonists — have become game changers for shedding excess pounds.

Aside from obesity indications, both drugs have been approved to treat type 2 diabetes under different brand names and have a growing list of other potential benefits, such as reducing inflammation and depression. 

These antiobesity drugs could even have a place in cancer care.

While there’s limited data to support the use of GLP-1 agonists for weight loss in cancer, some oncologists have begun carefully integrating the antiobesity agents into care and studying their effects in this patient population.

The reason: Research suggests that obesity can reduce the effectiveness of cancer therapies, especially in patients with breast cancer, and can increase the risk for treatment-related side effects. 

The idea is that managing patients’ weight will improve their cancer outcomes, explained Lajos Pusztai, MD, PhD, a breast cancer specialist and professor of medicine at Yale School of Medicine in New Haven, Connecticut. 

Although Dr. Pusztai and his oncology peers at Yale don’t yet use GPL-1 agonists, Neil Iyengar, MD, and colleagues have begun doing so to help some patients with breast cancer manage their weight. Dr. Iyengar estimates that a few hundred — almost 40% — of his patients are on the antiobesity drugs.

“For a patient who has really tried to reduce their weight and who is in the obese range, that’s where I think the use of these medications can be considered,” said Dr. Iyengar, a breast cancer oncologist at Memorial Sloan Kettering Cancer Center in New York City. 

Why GLP-1s in Cancer?

GLP-1 is a hormone that the small intestine releases after eating. GLP-1 agonists work by mimicking GLP-1 to trigger the release of insulin and reduce the production of glucagon — two processes that help regulate blood sugar. 

These agents, such as Wegovy (or Ozempic when prescribed for diabetes), also slow gastric emptying and can make people feel fuller longer. 

Zebound (or Mounjaro for type 2 diabetes) is considered a dual GLP-1 and glucose-dependent insulinotropic polypeptide agonist, which may enhance its weight loss benefits.

In practice, however, these drugs can increase nausea and vomiting from chemotherapy, so Dr. Iyengar typically has patients use them afterwards, during maintenance treatment.

Oncologists don’t prescribe the drugs themselves but instead refer patients to endocrinologists or weight management centers that then write the prescriptions. Taking these drugs involves weekly subcutaneous injections patients can administer themselves.

Endocrinologist Emily Gallagher, MD, PhD, of Mount Sinai Hospital in New York City, estimates she has prescribed the antiobesity drugs to a few hundred patients with cancer and, like Dr. Iyengar, uses the drugs during maintenance treatment with hormone therapy for breast cancer. She also has used these agents in patients with prostate and endometrial cancers and has found the drugs can help counter steroid weight gain in multiple myeloma. 

But, to date, the evidence for using GPL-1 agonists in cancer remains limited and the practice has not yet become widespread.

Research largely comes down to a few small retrospective studies in patients with breast cancer receiving aromatase inhibitors. Although no safety issues have emerged so far, these initial reports suggest that the drugs lead to significantly less weight loss in patients with cancer compared to the general population. 

Dr. Iyengar led one recent study, presented at the 2024 annual meeting of the American Society of Clinical Oncology, in which he and his team assessed outcomes in 75 women with breast cancer who received a GLP-1 agonist. Almost 80% of patients had diabetes, and 60% received hormone therapy, most commonly an aromatase inhibitor. Patients’ median body mass index (BMI) at baseline was 34 kg/m² (range, 23-50 kg/m²).

From baseline, patients lost 6.2 kg, on average, or about 5% of their total body weight, 12 months after initiating GLP-1 therapy. 

In contrast, phase 3 trials show much higher mean weight loss — about two times — in patients without cancer. 

Another recent study also reported modest weight loss results in patients with breast cancer undergoing endocrine therapy. The researchers reported that, at 12 months, Wegovy led to 4.34% reduction in BMI, compared with a 14% change reported in the general population. Zebound, however, was associated with a 2.31% BMI increase overall — though some patients did experience a decrease — compared with a 15% reduction in the general population. 

“These findings indicate a substantially reduced weight loss efficacy in breast cancer patients on endocrine therapy compared to the general population,” the authors concluded.

It’s unclear why the drugs appear to not work as well in patients with cancer. It’s possible that hormone therapy or metabolic changes interfere with their effectiveness, given that some cancer therapies lead to weight gain. Steroids and hormone therapies, for instance, often increase appetite, and some treatments can slow patients’ metabolism or lead to fatigue, which can make it harder to exercise.

Patients with cancer may need a higher dose of GLP-1 agonists to achieve similar weight loss to the general population, Dr. Iyengar noted.

However, Dr. Gallagher said, in her own experience, she hasn’t found the drugs to be less effective in patients with cancer, especially the newer agents, like Wegovy and Zepbound. 

As for safety, Wegovy and Zepbound both carry a black box warning for thyroid C-cell tumors, including medullary thyroid carcinoma. (Recent research, however, has found that GLP-1 agonists do not increase thyroid cancer risk). 

These antiobesity agents are also contraindicated in patients with a personal or family history of medullary thyroid carcinoma and in patients who have multiple endocrine neoplasia syndrome type 2, which is associated with medullary thyroid carcinoma.

Dr. Gallagher hasn’t seen any secondary tumors — thyroid or otherwise — in her patients with cancer, but she follows the labeling contraindications. Dr. Iyengar also noted that more recent and larger data sets have shown no impact on this risk, which may not actually exist, he said

Dr. Gallagher remains cautious about using GPL-1 agonists in patients who have had bariatric surgery because these agents can compound the slower gastric emptying and intestinal transit from surgery, potentially leading to gastrointestinal obstructions. 

Looking ahead, GPL-1 manufacturers are interested in adding cancer indications to the drug labeling. Both Dr. Iyengar and Dr. Gallagher said their institutions are in talks with companies to participate in large, multicenter, global phase 3 trials.

Dr. Iyengar welcomes the efforts, not only to test the effectiveness of GPL-1 agonists in oncology but also to “nail down” their safety in cancer. 

“I don’t think that there’s mechanistically anything that’s particularly worrisome,” and current observations suggest that these drugs are likely to be safe, Dr. Iyengar said. Even so, “GLP-1 agonists do a lot of things that we don’t fully understand yet.”

The bigger challenge, Dr. Iyengar noted, is that companies will have to show a sizable benefit to using these drugs in patients with cancer to get the Food and Drug Administration’s approval. And to move the needle on cancer-specific outcomes, these antiobesity drugs will need to demonstrate significant, durable weight loss in patients with cancer. 

But if these drugs can do that, “I think it’s going to be one of the biggest advances in medicine and oncology given the obesity and cancer epidemic,” Dr. Iyengar said. 

Dr. Iyengar has adviser and/or researcher ties with companies that make or are developing GPL-1 agonists, including AstraZeneca, Novartis, Gilead, and Pfizer. Dr. Gallagher is a consultant for Novartis, Flare Therapeutics, Reactive Biosciences, and Seagen.

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

Demand for new weight loss drugs has surged over the past few years. 

Led by the antiobesity drugs semaglutide (Wegovy) and tirzepatide (Zepbound), these popular medications — more commonly known as glucagon-like peptide 1 (GLP-1) agonists — have become game changers for shedding excess pounds.

Aside from obesity indications, both drugs have been approved to treat type 2 diabetes under different brand names and have a growing list of other potential benefits, such as reducing inflammation and depression. 

These antiobesity drugs could even have a place in cancer care.

While there’s limited data to support the use of GLP-1 agonists for weight loss in cancer, some oncologists have begun carefully integrating the antiobesity agents into care and studying their effects in this patient population.

The reason: Research suggests that obesity can reduce the effectiveness of cancer therapies, especially in patients with breast cancer, and can increase the risk for treatment-related side effects. 

The idea is that managing patients’ weight will improve their cancer outcomes, explained Lajos Pusztai, MD, PhD, a breast cancer specialist and professor of medicine at Yale School of Medicine in New Haven, Connecticut. 

Although Dr. Pusztai and his oncology peers at Yale don’t yet use GPL-1 agonists, Neil Iyengar, MD, and colleagues have begun doing so to help some patients with breast cancer manage their weight. Dr. Iyengar estimates that a few hundred — almost 40% — of his patients are on the antiobesity drugs.

“For a patient who has really tried to reduce their weight and who is in the obese range, that’s where I think the use of these medications can be considered,” said Dr. Iyengar, a breast cancer oncologist at Memorial Sloan Kettering Cancer Center in New York City. 

Why GLP-1s in Cancer?

GLP-1 is a hormone that the small intestine releases after eating. GLP-1 agonists work by mimicking GLP-1 to trigger the release of insulin and reduce the production of glucagon — two processes that help regulate blood sugar. 

These agents, such as Wegovy (or Ozempic when prescribed for diabetes), also slow gastric emptying and can make people feel fuller longer. 

Zebound (or Mounjaro for type 2 diabetes) is considered a dual GLP-1 and glucose-dependent insulinotropic polypeptide agonist, which may enhance its weight loss benefits.

In practice, however, these drugs can increase nausea and vomiting from chemotherapy, so Dr. Iyengar typically has patients use them afterwards, during maintenance treatment.

Oncologists don’t prescribe the drugs themselves but instead refer patients to endocrinologists or weight management centers that then write the prescriptions. Taking these drugs involves weekly subcutaneous injections patients can administer themselves.

Endocrinologist Emily Gallagher, MD, PhD, of Mount Sinai Hospital in New York City, estimates she has prescribed the antiobesity drugs to a few hundred patients with cancer and, like Dr. Iyengar, uses the drugs during maintenance treatment with hormone therapy for breast cancer. She also has used these agents in patients with prostate and endometrial cancers and has found the drugs can help counter steroid weight gain in multiple myeloma. 

But, to date, the evidence for using GPL-1 agonists in cancer remains limited and the practice has not yet become widespread.

Research largely comes down to a few small retrospective studies in patients with breast cancer receiving aromatase inhibitors. Although no safety issues have emerged so far, these initial reports suggest that the drugs lead to significantly less weight loss in patients with cancer compared to the general population. 

Dr. Iyengar led one recent study, presented at the 2024 annual meeting of the American Society of Clinical Oncology, in which he and his team assessed outcomes in 75 women with breast cancer who received a GLP-1 agonist. Almost 80% of patients had diabetes, and 60% received hormone therapy, most commonly an aromatase inhibitor. Patients’ median body mass index (BMI) at baseline was 34 kg/m² (range, 23-50 kg/m²).

From baseline, patients lost 6.2 kg, on average, or about 5% of their total body weight, 12 months after initiating GLP-1 therapy. 

In contrast, phase 3 trials show much higher mean weight loss — about two times — in patients without cancer. 

Another recent study also reported modest weight loss results in patients with breast cancer undergoing endocrine therapy. The researchers reported that, at 12 months, Wegovy led to 4.34% reduction in BMI, compared with a 14% change reported in the general population. Zebound, however, was associated with a 2.31% BMI increase overall — though some patients did experience a decrease — compared with a 15% reduction in the general population. 

“These findings indicate a substantially reduced weight loss efficacy in breast cancer patients on endocrine therapy compared to the general population,” the authors concluded.

It’s unclear why the drugs appear to not work as well in patients with cancer. It’s possible that hormone therapy or metabolic changes interfere with their effectiveness, given that some cancer therapies lead to weight gain. Steroids and hormone therapies, for instance, often increase appetite, and some treatments can slow patients’ metabolism or lead to fatigue, which can make it harder to exercise.

Patients with cancer may need a higher dose of GLP-1 agonists to achieve similar weight loss to the general population, Dr. Iyengar noted.

However, Dr. Gallagher said, in her own experience, she hasn’t found the drugs to be less effective in patients with cancer, especially the newer agents, like Wegovy and Zepbound. 

As for safety, Wegovy and Zepbound both carry a black box warning for thyroid C-cell tumors, including medullary thyroid carcinoma. (Recent research, however, has found that GLP-1 agonists do not increase thyroid cancer risk). 

These antiobesity agents are also contraindicated in patients with a personal or family history of medullary thyroid carcinoma and in patients who have multiple endocrine neoplasia syndrome type 2, which is associated with medullary thyroid carcinoma.

Dr. Gallagher hasn’t seen any secondary tumors — thyroid or otherwise — in her patients with cancer, but she follows the labeling contraindications. Dr. Iyengar also noted that more recent and larger data sets have shown no impact on this risk, which may not actually exist, he said

Dr. Gallagher remains cautious about using GPL-1 agonists in patients who have had bariatric surgery because these agents can compound the slower gastric emptying and intestinal transit from surgery, potentially leading to gastrointestinal obstructions. 

Looking ahead, GPL-1 manufacturers are interested in adding cancer indications to the drug labeling. Both Dr. Iyengar and Dr. Gallagher said their institutions are in talks with companies to participate in large, multicenter, global phase 3 trials.

Dr. Iyengar welcomes the efforts, not only to test the effectiveness of GPL-1 agonists in oncology but also to “nail down” their safety in cancer. 

“I don’t think that there’s mechanistically anything that’s particularly worrisome,” and current observations suggest that these drugs are likely to be safe, Dr. Iyengar said. Even so, “GLP-1 agonists do a lot of things that we don’t fully understand yet.”

The bigger challenge, Dr. Iyengar noted, is that companies will have to show a sizable benefit to using these drugs in patients with cancer to get the Food and Drug Administration’s approval. And to move the needle on cancer-specific outcomes, these antiobesity drugs will need to demonstrate significant, durable weight loss in patients with cancer. 

But if these drugs can do that, “I think it’s going to be one of the biggest advances in medicine and oncology given the obesity and cancer epidemic,” Dr. Iyengar said. 

Dr. Iyengar has adviser and/or researcher ties with companies that make or are developing GPL-1 agonists, including AstraZeneca, Novartis, Gilead, and Pfizer. Dr. Gallagher is a consultant for Novartis, Flare Therapeutics, Reactive Biosciences, and Seagen.

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

Demand for new weight loss drugs has surged over the past few years. 

Led by the antiobesity drugs semaglutide (Wegovy) and tirzepatide (Zepbound), these popular medications — more commonly known as glucagon-like peptide 1 (GLP-1) agonists — have become game changers for shedding excess pounds.

Aside from obesity indications, both drugs have been approved to treat type 2 diabetes under different brand names and have a growing list of other potential benefits, such as reducing inflammation and depression. 

These antiobesity drugs could even have a place in cancer care.

While there’s limited data to support the use of GLP-1 agonists for weight loss in cancer, some oncologists have begun carefully integrating the antiobesity agents into care and studying their effects in this patient population.

The reason: Research suggests that obesity can reduce the effectiveness of cancer therapies, especially in patients with breast cancer, and can increase the risk for treatment-related side effects. 

The idea is that managing patients’ weight will improve their cancer outcomes, explained Lajos Pusztai, MD, PhD, a breast cancer specialist and professor of medicine at Yale School of Medicine in New Haven, Connecticut. 

Although Dr. Pusztai and his oncology peers at Yale don’t yet use GPL-1 agonists, Neil Iyengar, MD, and colleagues have begun doing so to help some patients with breast cancer manage their weight. Dr. Iyengar estimates that a few hundred — almost 40% — of his patients are on the antiobesity drugs.

“For a patient who has really tried to reduce their weight and who is in the obese range, that’s where I think the use of these medications can be considered,” said Dr. Iyengar, a breast cancer oncologist at Memorial Sloan Kettering Cancer Center in New York City. 

Why GLP-1s in Cancer?

GLP-1 is a hormone that the small intestine releases after eating. GLP-1 agonists work by mimicking GLP-1 to trigger the release of insulin and reduce the production of glucagon — two processes that help regulate blood sugar. 

These agents, such as Wegovy (or Ozempic when prescribed for diabetes), also slow gastric emptying and can make people feel fuller longer. 

Zebound (or Mounjaro for type 2 diabetes) is considered a dual GLP-1 and glucose-dependent insulinotropic polypeptide agonist, which may enhance its weight loss benefits.

In practice, however, these drugs can increase nausea and vomiting from chemotherapy, so Dr. Iyengar typically has patients use them afterwards, during maintenance treatment.

Oncologists don’t prescribe the drugs themselves but instead refer patients to endocrinologists or weight management centers that then write the prescriptions. Taking these drugs involves weekly subcutaneous injections patients can administer themselves.

Endocrinologist Emily Gallagher, MD, PhD, of Mount Sinai Hospital in New York City, estimates she has prescribed the antiobesity drugs to a few hundred patients with cancer and, like Dr. Iyengar, uses the drugs during maintenance treatment with hormone therapy for breast cancer. She also has used these agents in patients with prostate and endometrial cancers and has found the drugs can help counter steroid weight gain in multiple myeloma. 

But, to date, the evidence for using GPL-1 agonists in cancer remains limited and the practice has not yet become widespread.

Research largely comes down to a few small retrospective studies in patients with breast cancer receiving aromatase inhibitors. Although no safety issues have emerged so far, these initial reports suggest that the drugs lead to significantly less weight loss in patients with cancer compared to the general population. 

Dr. Iyengar led one recent study, presented at the 2024 annual meeting of the American Society of Clinical Oncology, in which he and his team assessed outcomes in 75 women with breast cancer who received a GLP-1 agonist. Almost 80% of patients had diabetes, and 60% received hormone therapy, most commonly an aromatase inhibitor. Patients’ median body mass index (BMI) at baseline was 34 kg/m² (range, 23-50 kg/m²).

From baseline, patients lost 6.2 kg, on average, or about 5% of their total body weight, 12 months after initiating GLP-1 therapy. 

In contrast, phase 3 trials show much higher mean weight loss — about two times — in patients without cancer. 

Another recent study also reported modest weight loss results in patients with breast cancer undergoing endocrine therapy. The researchers reported that, at 12 months, Wegovy led to 4.34% reduction in BMI, compared with a 14% change reported in the general population. Zebound, however, was associated with a 2.31% BMI increase overall — though some patients did experience a decrease — compared with a 15% reduction in the general population. 

“These findings indicate a substantially reduced weight loss efficacy in breast cancer patients on endocrine therapy compared to the general population,” the authors concluded.

It’s unclear why the drugs appear to not work as well in patients with cancer. It’s possible that hormone therapy or metabolic changes interfere with their effectiveness, given that some cancer therapies lead to weight gain. Steroids and hormone therapies, for instance, often increase appetite, and some treatments can slow patients’ metabolism or lead to fatigue, which can make it harder to exercise.

Patients with cancer may need a higher dose of GLP-1 agonists to achieve similar weight loss to the general population, Dr. Iyengar noted.

However, Dr. Gallagher said, in her own experience, she hasn’t found the drugs to be less effective in patients with cancer, especially the newer agents, like Wegovy and Zepbound. 

As for safety, Wegovy and Zepbound both carry a black box warning for thyroid C-cell tumors, including medullary thyroid carcinoma. (Recent research, however, has found that GLP-1 agonists do not increase thyroid cancer risk). 

These antiobesity agents are also contraindicated in patients with a personal or family history of medullary thyroid carcinoma and in patients who have multiple endocrine neoplasia syndrome type 2, which is associated with medullary thyroid carcinoma.

Dr. Gallagher hasn’t seen any secondary tumors — thyroid or otherwise — in her patients with cancer, but she follows the labeling contraindications. Dr. Iyengar also noted that more recent and larger data sets have shown no impact on this risk, which may not actually exist, he said

Dr. Gallagher remains cautious about using GPL-1 agonists in patients who have had bariatric surgery because these agents can compound the slower gastric emptying and intestinal transit from surgery, potentially leading to gastrointestinal obstructions. 

Looking ahead, GPL-1 manufacturers are interested in adding cancer indications to the drug labeling. Both Dr. Iyengar and Dr. Gallagher said their institutions are in talks with companies to participate in large, multicenter, global phase 3 trials.

Dr. Iyengar welcomes the efforts, not only to test the effectiveness of GPL-1 agonists in oncology but also to “nail down” their safety in cancer. 

“I don’t think that there’s mechanistically anything that’s particularly worrisome,” and current observations suggest that these drugs are likely to be safe, Dr. Iyengar said. Even so, “GLP-1 agonists do a lot of things that we don’t fully understand yet.”

The bigger challenge, Dr. Iyengar noted, is that companies will have to show a sizable benefit to using these drugs in patients with cancer to get the Food and Drug Administration’s approval. And to move the needle on cancer-specific outcomes, these antiobesity drugs will need to demonstrate significant, durable weight loss in patients with cancer. 

But if these drugs can do that, “I think it’s going to be one of the biggest advances in medicine and oncology given the obesity and cancer epidemic,” Dr. Iyengar said. 

Dr. Iyengar has adviser and/or researcher ties with companies that make or are developing GPL-1 agonists, including AstraZeneca, Novartis, Gilead, and Pfizer. Dr. Gallagher is a consultant for Novartis, Flare Therapeutics, Reactive Biosciences, and Seagen.

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

Eliezer Masliah, MD, director of the neuroscience division at the National Institute on Aging (NIA), has been “relieved of his position” following an investigation by the National Institutes of Health (NIH) that turned up research misconduct, the NIH said in a statement.

The misconduct involved “falsification and/or fabrication involving reuse and relabel of figure panels representing different experimental results in two publications,” the NIH said.

The agency said it will notify the two journals of its findings so that appropriate action can be taken.

The NIH reportedly launched its probe into potential research misconduct in May 2023 after it received allegations from the Health and Human Service (HHS) Office of Research Integrity (ORI) that month.

The investigation phase began in December 2023 and concluded on September 15, 2024. The institute subsequently notified HHS ORI of its findings.

Dr. Masliah joined the NIH in the summer of 2016 as director of the Division of Neuroscience at the NIA and an NIH intramural researcher investigating synaptic damage in neurodegenerative disorders, publishing “numerous” papers, the NIH said.

Given the findings of their investigation, the NIH said, Dr. Masliah is no longer serving as director of NIA’s Division of Neuroscience.

NIA deputy director Amy Kelley, MD, is now acting director of NIA’s neuroscience division.

Consistent with NIH policies and procedures, any allegations involving Dr. Masliah’s NIH-supported extramural research prior to joining NIH would be referred to HHS ORI, the NIH said.

The NIH announcement came on the same day that Science magazine published an investigative piece suggesting that Dr. Masliah may have fabricated or falsified images or other information in far more than the two studies NIH cited.

According to the article, “scores” of Dr. Masliah’s lab studies conducted at the NIA and the University of California San Diego are “riddled with apparently falsified Western blots — images used to show the presence of proteins — and micrographs of brain tissue. Numerous images seem to have been inappropriately reused within and across papers, sometimes published years apart in different journals, describing divergent experimental conditions.”

The article noted that a neuroscientist and forensic analysts who had previously worked with Science magazine produced a “300-page dossier revealing a steady stream of suspect images between 1997 and 2023 in 132 of his published research papers.”

They concluded that this “pattern of anomalous data raises a credible concern for research misconduct and calls into question a remarkably large body of scientific work,” the Science article stated.
 

A version of this article appeared on Medscape.com.

Eliezer Masliah, MD, director of the neuroscience division at the National Institute on Aging (NIA), has been “relieved of his position” following an investigation by the National Institutes of Health (NIH) that turned up research misconduct, the NIH said in a statement.

The misconduct involved “falsification and/or fabrication involving reuse and relabel of figure panels representing different experimental results in two publications,” the NIH said.

The agency said it will notify the two journals of its findings so that appropriate action can be taken.

The NIH reportedly launched its probe into potential research misconduct in May 2023 after it received allegations from the Health and Human Service (HHS) Office of Research Integrity (ORI) that month.

The investigation phase began in December 2023 and concluded on September 15, 2024. The institute subsequently notified HHS ORI of its findings.

Dr. Masliah joined the NIH in the summer of 2016 as director of the Division of Neuroscience at the NIA and an NIH intramural researcher investigating synaptic damage in neurodegenerative disorders, publishing “numerous” papers, the NIH said.

Given the findings of their investigation, the NIH said, Dr. Masliah is no longer serving as director of NIA’s Division of Neuroscience.

NIA deputy director Amy Kelley, MD, is now acting director of NIA’s neuroscience division.

Consistent with NIH policies and procedures, any allegations involving Dr. Masliah’s NIH-supported extramural research prior to joining NIH would be referred to HHS ORI, the NIH said.

The NIH announcement came on the same day that Science magazine published an investigative piece suggesting that Dr. Masliah may have fabricated or falsified images or other information in far more than the two studies NIH cited.

According to the article, “scores” of Dr. Masliah’s lab studies conducted at the NIA and the University of California San Diego are “riddled with apparently falsified Western blots — images used to show the presence of proteins — and micrographs of brain tissue. Numerous images seem to have been inappropriately reused within and across papers, sometimes published years apart in different journals, describing divergent experimental conditions.”

The article noted that a neuroscientist and forensic analysts who had previously worked with Science magazine produced a “300-page dossier revealing a steady stream of suspect images between 1997 and 2023 in 132 of his published research papers.”

They concluded that this “pattern of anomalous data raises a credible concern for research misconduct and calls into question a remarkably large body of scientific work,” the Science article stated.
 

A version of this article appeared on Medscape.com.

Eliezer Masliah, MD, director of the neuroscience division at the National Institute on Aging (NIA), has been “relieved of his position” following an investigation by the National Institutes of Health (NIH) that turned up research misconduct, the NIH said in a statement.

The misconduct involved “falsification and/or fabrication involving reuse and relabel of figure panels representing different experimental results in two publications,” the NIH said.

The agency said it will notify the two journals of its findings so that appropriate action can be taken.

The NIH reportedly launched its probe into potential research misconduct in May 2023 after it received allegations from the Health and Human Service (HHS) Office of Research Integrity (ORI) that month.

The investigation phase began in December 2023 and concluded on September 15, 2024. The institute subsequently notified HHS ORI of its findings.

Dr. Masliah joined the NIH in the summer of 2016 as director of the Division of Neuroscience at the NIA and an NIH intramural researcher investigating synaptic damage in neurodegenerative disorders, publishing “numerous” papers, the NIH said.

Given the findings of their investigation, the NIH said, Dr. Masliah is no longer serving as director of NIA’s Division of Neuroscience.

NIA deputy director Amy Kelley, MD, is now acting director of NIA’s neuroscience division.

Consistent with NIH policies and procedures, any allegations involving Dr. Masliah’s NIH-supported extramural research prior to joining NIH would be referred to HHS ORI, the NIH said.

The NIH announcement came on the same day that Science magazine published an investigative piece suggesting that Dr. Masliah may have fabricated or falsified images or other information in far more than the two studies NIH cited.

According to the article, “scores” of Dr. Masliah’s lab studies conducted at the NIA and the University of California San Diego are “riddled with apparently falsified Western blots — images used to show the presence of proteins — and micrographs of brain tissue. Numerous images seem to have been inappropriately reused within and across papers, sometimes published years apart in different journals, describing divergent experimental conditions.”

The article noted that a neuroscientist and forensic analysts who had previously worked with Science magazine produced a “300-page dossier revealing a steady stream of suspect images between 1997 and 2023 in 132 of his published research papers.”

They concluded that this “pattern of anomalous data raises a credible concern for research misconduct and calls into question a remarkably large body of scientific work,” the Science article stated.
 

A version of this article appeared on Medscape.com.

EDITOR’S NOTE

This year, we again focus on rare neurological diseases that have new therapies that have been recently approved as well as conditions for which the treatment pipeline is robust. Let’s hope the work of many dedicated researchers adds to the list of rare neurological diseases for which treatment is available.

This year also marks a change of leadership at NORD, our publishing partner in this annual supplement. We here at Neurology Reviews salute the leadership and accomplishments of former NORD CEO Peter Saltonstall and also welcome incoming CEO Pamela Gavin, who has spent many years in NORD leadership roles and was essential in the planning, launch, and early years of this annual supplement. I can think of no one better than Pamela Gavin to continue NORD’s mission into the future.

And finally, a recap of accolades for this annual supplement. For the second year in a row, the Rare Neurological Disease Special Report has won an Azbee award in the category of annual supplement from the American Society of Business Publication Editors. The 2023 issue won a National Gold Award and a Regional Gold Award.

—Glenn Williams, VP, Group Editor, Neurology Reviews and MDedge Neurology

A NOTE FROM NORD

Hello, and Welcome! The National Organization for Rare Disorders (NORD) is pleased to partner with Neurology Reviews to bring you the 2024 edition of the Rare Neurological Disease Report. Through this collaboration, we share cutting-edge research and insights from leading medical experts, including specialists from the NORD Rare Disease Centers of Excellence network, about the latest advances in the treatment of rare neurological conditions.

As healthcare providers, you play a key role in catalyzing advancements and bringing new hope and possibilities to the rare disease community. Your efforts can contribute to shortening the diagnostic odyssey and improving day-to-day care for people living with rare disorders in crucial ways:

Identifying patients: Healthcare providers can recognize the possible signs of a rare disease and initiate further investigation or referral to specialists. Early detection is key as it can lead to a quicker, more accurate diagnosis, better management, and improved outcomes.

Educating other physicians: Many rare diseases are not well-known or understood by the general medical community. Healthcare providers can help bridge this knowledge gap by educating other physicians about rare conditions. They can raise awareness through clinical teaching, seminars, medical literature, or continuing medical education (CME) sessions focused on rare diseases. Raising awareness and providing up-to-date information about rare diseases bolsters diagnostic and treatment capabilities within the medical field.

Providing information to patients: Once a rare disease is identified, healthcare providers can offer valuable support to patients and their families. They can provide potential treatments and management strategies. They can also connect patients with support groups, support programs, educational resources, and specialists with expertise in specific rare conditions. Clear communication and guidance on support resources can positively impact patients’ well-being, empower them to make informed decisions, and help them navigate a complex rare condition.

This issue of the Rare Disease Neurological Special Report features articles by rare disease medical experts on specific diseases with updates on clinical management. Topics include the diagnosis and management of Duchenne muscular dystrophy, the promise of disease-modifying therapies for Huntington’s disease, patient choices and cultural changes around myasthenia gravis, advances in neuromyelitis optica, and untangling chronic inflammatory demyelinating polyneuropathy. In addition, two online-only articles offer timely insights from key opinion leaders on the pros and cons of genetic testing and what clinicians need to know about newborn screening.

You will also find information about the NORD Rare Diseases and Orphan Products Breakthrough Summit. This annual event convenes thought leaders from patient advocacy organizations, industry, academia, medical and research institutions, and government to discuss critical topics facing the rare disease community. 

NORD is deeply appreciative of healthcare professionals like you, who despite long hours and demanding workloads, remain committed to staying up to date on the latest medical advances for the benefit of their patients. Your dedication and hard work make a significant difference to the patients and families we serve, and your commitment does not go unnoticed. Thank you for all that you do.

—Pamela Gavin, NORD Chief Executive Officer

EDITOR’S NOTE

This year, we again focus on rare neurological diseases that have new therapies that have been recently approved as well as conditions for which the treatment pipeline is robust. Let’s hope the work of many dedicated researchers adds to the list of rare neurological diseases for which treatment is available.

This year also marks a change of leadership at NORD, our publishing partner in this annual supplement. We here at Neurology Reviews salute the leadership and accomplishments of former NORD CEO Peter Saltonstall and also welcome incoming CEO Pamela Gavin, who has spent many years in NORD leadership roles and was essential in the planning, launch, and early years of this annual supplement. I can think of no one better than Pamela Gavin to continue NORD’s mission into the future.

And finally, a recap of accolades for this annual supplement. For the second year in a row, the Rare Neurological Disease Special Report has won an Azbee award in the category of annual supplement from the American Society of Business Publication Editors. The 2023 issue won a National Gold Award and a Regional Gold Award.

—Glenn Williams, VP, Group Editor, Neurology Reviews and MDedge Neurology

A NOTE FROM NORD

Hello, and Welcome! The National Organization for Rare Disorders (NORD) is pleased to partner with Neurology Reviews to bring you the 2024 edition of the Rare Neurological Disease Report. Through this collaboration, we share cutting-edge research and insights from leading medical experts, including specialists from the NORD Rare Disease Centers of Excellence network, about the latest advances in the treatment of rare neurological conditions.

As healthcare providers, you play a key role in catalyzing advancements and bringing new hope and possibilities to the rare disease community. Your efforts can contribute to shortening the diagnostic odyssey and improving day-to-day care for people living with rare disorders in crucial ways:

Identifying patients: Healthcare providers can recognize the possible signs of a rare disease and initiate further investigation or referral to specialists. Early detection is key as it can lead to a quicker, more accurate diagnosis, better management, and improved outcomes.

Educating other physicians: Many rare diseases are not well-known or understood by the general medical community. Healthcare providers can help bridge this knowledge gap by educating other physicians about rare conditions. They can raise awareness through clinical teaching, seminars, medical literature, or continuing medical education (CME) sessions focused on rare diseases. Raising awareness and providing up-to-date information about rare diseases bolsters diagnostic and treatment capabilities within the medical field.

Providing information to patients: Once a rare disease is identified, healthcare providers can offer valuable support to patients and their families. They can provide potential treatments and management strategies. They can also connect patients with support groups, support programs, educational resources, and specialists with expertise in specific rare conditions. Clear communication and guidance on support resources can positively impact patients’ well-being, empower them to make informed decisions, and help them navigate a complex rare condition.

This issue of the Rare Disease Neurological Special Report features articles by rare disease medical experts on specific diseases with updates on clinical management. Topics include the diagnosis and management of Duchenne muscular dystrophy, the promise of disease-modifying therapies for Huntington’s disease, patient choices and cultural changes around myasthenia gravis, advances in neuromyelitis optica, and untangling chronic inflammatory demyelinating polyneuropathy. In addition, two online-only articles offer timely insights from key opinion leaders on the pros and cons of genetic testing and what clinicians need to know about newborn screening.

You will also find information about the NORD Rare Diseases and Orphan Products Breakthrough Summit. This annual event convenes thought leaders from patient advocacy organizations, industry, academia, medical and research institutions, and government to discuss critical topics facing the rare disease community. 

NORD is deeply appreciative of healthcare professionals like you, who despite long hours and demanding workloads, remain committed to staying up to date on the latest medical advances for the benefit of their patients. Your dedication and hard work make a significant difference to the patients and families we serve, and your commitment does not go unnoticed. Thank you for all that you do.

—Pamela Gavin, NORD Chief Executive Officer

EDITOR’S NOTE

This year, we again focus on rare neurological diseases that have new therapies that have been recently approved as well as conditions for which the treatment pipeline is robust. Let’s hope the work of many dedicated researchers adds to the list of rare neurological diseases for which treatment is available.

This year also marks a change of leadership at NORD, our publishing partner in this annual supplement. We here at Neurology Reviews salute the leadership and accomplishments of former NORD CEO Peter Saltonstall and also welcome incoming CEO Pamela Gavin, who has spent many years in NORD leadership roles and was essential in the planning, launch, and early years of this annual supplement. I can think of no one better than Pamela Gavin to continue NORD’s mission into the future.

And finally, a recap of accolades for this annual supplement. For the second year in a row, the Rare Neurological Disease Special Report has won an Azbee award in the category of annual supplement from the American Society of Business Publication Editors. The 2023 issue won a National Gold Award and a Regional Gold Award.

—Glenn Williams, VP, Group Editor, Neurology Reviews and MDedge Neurology

A NOTE FROM NORD

Hello, and Welcome! The National Organization for Rare Disorders (NORD) is pleased to partner with Neurology Reviews to bring you the 2024 edition of the Rare Neurological Disease Report. Through this collaboration, we share cutting-edge research and insights from leading medical experts, including specialists from the NORD Rare Disease Centers of Excellence network, about the latest advances in the treatment of rare neurological conditions.

As healthcare providers, you play a key role in catalyzing advancements and bringing new hope and possibilities to the rare disease community. Your efforts can contribute to shortening the diagnostic odyssey and improving day-to-day care for people living with rare disorders in crucial ways:

Identifying patients: Healthcare providers can recognize the possible signs of a rare disease and initiate further investigation or referral to specialists. Early detection is key as it can lead to a quicker, more accurate diagnosis, better management, and improved outcomes.

Educating other physicians: Many rare diseases are not well-known or understood by the general medical community. Healthcare providers can help bridge this knowledge gap by educating other physicians about rare conditions. They can raise awareness through clinical teaching, seminars, medical literature, or continuing medical education (CME) sessions focused on rare diseases. Raising awareness and providing up-to-date information about rare diseases bolsters diagnostic and treatment capabilities within the medical field.

Providing information to patients: Once a rare disease is identified, healthcare providers can offer valuable support to patients and their families. They can provide potential treatments and management strategies. They can also connect patients with support groups, support programs, educational resources, and specialists with expertise in specific rare conditions. Clear communication and guidance on support resources can positively impact patients’ well-being, empower them to make informed decisions, and help them navigate a complex rare condition.

This issue of the Rare Disease Neurological Special Report features articles by rare disease medical experts on specific diseases with updates on clinical management. Topics include the diagnosis and management of Duchenne muscular dystrophy, the promise of disease-modifying therapies for Huntington’s disease, patient choices and cultural changes around myasthenia gravis, advances in neuromyelitis optica, and untangling chronic inflammatory demyelinating polyneuropathy. In addition, two online-only articles offer timely insights from key opinion leaders on the pros and cons of genetic testing and what clinicians need to know about newborn screening.

You will also find information about the NORD Rare Diseases and Orphan Products Breakthrough Summit. This annual event convenes thought leaders from patient advocacy organizations, industry, academia, medical and research institutions, and government to discuss critical topics facing the rare disease community. 

NORD is deeply appreciative of healthcare professionals like you, who despite long hours and demanding workloads, remain committed to staying up to date on the latest medical advances for the benefit of their patients. Your dedication and hard work make a significant difference to the patients and families we serve, and your commitment does not go unnoticed. Thank you for all that you do.

—Pamela Gavin, NORD Chief Executive Officer

The overwhelming majority of rare diseases have a genetic origin, with estimates varying from 71.9% to 80% of rare diseases. Although a rare disease is defined as a condition that affects fewer than 200,000 people domestically, collectively, rare diseases impact approximately 30 million US residents, with at least one of the more than 7,000 rare genetic disorders. In fact, the population of patients with at least one rare disease mirrors the prevalence of people who have type 2 diabetes, or one in every 10 people. Despite their prevalence, most rare conditions are treated only when symptomatic, as many cases remain either misdiagnosed or undiagnosed. As with most health conditions, it is imperative to have a prompt and accurate diagnosis to improve outcomes and avoid inappropriate or unnecessary treatments that may pose severe side effects to the patient.

As the push toward prompt testing and treatment of rare diseases continues building momentum, it has cast a growing spotlight on genetic testing and its potential. To that end, this report weighs the less obvious pros and cons of genetic testing in rare diseases of which neurologists should be aware.
 

The Path to Accurate Diagnosis Remains Long Despite Increased Genetic Testing

When it comes to identifying the greatest challenge in rare genetic disease testing for the neurology community, experts have different opinions. For Kiley Boone Quintana, MD, assistant professor of pediatrics at the University of New Mexico in Albuquerque, the greatest challenge for neurologists navigating this space lies in becoming comfortable with the unknown.

“Many neurologists think genetic testing will certainly find an answer or that the answers will be black and white — which is not true,” said Dr. Quintana. “Instead of clear answers, we often find variants of unknown significance and genetic changes like a deletion or duplication that can have reduced penetrance, so clinicians have to become comfortable with not always having an answer or not knowing exactly how the answer will impact the person.”

Whole Exome and Whole Genome Testing Continues Growing in Prevalence, But Neither Offers a Panacea

Historically, genetic testing was expensive, with only a few genes interrogated at a time. However, the past decade has seen prices simmer down with the introduction of next-generation sequencing — a technology that improves both the accuracy and utility of genetic testing.

One form of genetic testing, called whole exome sequencing, has proven especially helpful in recent years because it looks at all 20,000 genes and spelling changes that can cause mutations and genetic diseases. However, whole exome testing comes with its own limitations. It tests at the DNA loci that produce the actual protein blueprints but does not look at the DNA between those spaces. In addition, the medical community lacks a comprehensive understanding of all 20,000 genes, as scientists have yet to understand all their functions.

Unfortunately, the drawbacks do not stop there.

“Whole exome sequencing is not good at detecting conditions such as Huntington’s disease or Fragile X syndrome,” Dr. Quintana said. “It also fails to pick up spelling changes in DNA of noncoding regions, which we are learning do have functions in epigenetics.”

Quality also can limit reliability of both exome and genome testing. According to Dr. Regier, trustworthiness of results depends on several factors, including the lab conducting the test and the analysis performed. To help ensure quality, Dr. Regier and her colleagues use only CLIA-certified labs and labs that follow the American College of Medical Genetics (ACMG) guidelines. Furthermore, they allow only qualified experts to analyze the results, experts who hold board certifications with either the American College of Medical Genetics and Genomics or the American Board of Pathology.
 

Familial and Societal Stigma Surrounding Rare Diseases Engenders Emotional, Psychological, and Financial Distress

Ultimately, traversing the trajectory of delayed diagnosis and its ambiguity also leaves questions regarding how it will impact the person. All too often, these mysteries transcend the patient with the condition, affecting relatives and other loved ones, as the familial and societal stigma surrounding rare diseases engenders emotional and psychological distress.

In cases with prolonged or delayed diagnostics, Dr. Quintana said that neurologists should advise patients to prepare themselves for the potential of arduous workups — some of which may also come at a high price. Not only does a circuitous path to diagnosis impede treatment initiation, but it often results in major trauma for patients and their caregivers, who encounter significant emotional, psychological, and financial distress in the fallout. Emotional distress of misdiagnosis or lack of a diagnosis remains a significant pain point for patients and their family members alike.

Emotional distress presents the greatest drawback for the rare disease community, according to Dr. Regier. She described the cons of navigating a rare genetic disease diagnosis as “very personal” for families.

“Sometimes, there can be guilt or shame associated with a genetic illness,” Dr. Regier noted. “Understanding the ‘why’ or knowing better how to use nonspecific treatments can be incredibly important to reduce guilt and shame, but it also allows the family to feel like there is a reason and encourages inclusion in the social setting.”

Diagnosis typically results in inclusion in a patient and family group, which increases understanding while easing some of the psychological and emotional stress associated with not knowing the cause.
 

Establishing Social Support Networks Typically Falls on the Patient and Loved Ones

Another con in rare genetic diseases is the lack of adoption across the community.

Because of the long haul, neurologists and other clinicians should recognize the need for patients to have support. Both Dr. Regier and Dr. Quintana agreed that communal support is a critical component of managing the rare genetic disease population. However, finding one’s tribe is easier said than done. Due to the diagnostic hurdles and low number of people with confirmed diagnoses, patient communities and patient advocacy groups for people with individual rare diseases can be underdeveloped. However, the importance of family-based support groups should not be understated. The low community head counts and high level of time investment for care also contributes to poor recruitment turnouts for clinical trials and, subsequently, the sparse number of therapies for such conditions in the pipeline. However, it is also worth noting that, in the case of rare diseases, insufficient disease state knowledge, antiquated policies, lack of funding, and poor research and development diagnostic infrastructure also amplify such cons.

Patients can form communities of support by finding other families and knowing what to expect in terms of complications. While clinicians may not always have the resources to help the patient establish support systems, they can increase the patients’ awareness and encourage them to search for groups that align with their needs. Dr. Quintana reported that many of her patients find support groups of people with the same rare conditions through social media outlets such as Facebook.
 

Lack of Widespread Genetic Testing Adoption Remains a Barrier in Rare Diseases

As Dr. Quintana told Neurology Reviews, geneticists are more likely to order exome testing, despite the fact that genome-wide testing is slightly more likely to find a diagnosis. However, she anticipates that genome-wide testing will gain wider adoption in the future.

In terms of cost and feasibility, genetic testing can identify roughly 50% of the underlying etiology of a rare disease, including phenotyping to make a clinical diagnosis and using genetic testing, according to Dr. Regier.

Regarding the broad use of whole genome sequencing, Dr. Regier foresees that the more we learn about all the diagnostic and prognostic information rare disease testing can give us, “the more this number will grow.”

As an example of the true impact, she shared how new research indicates that changes to one’s DNA can lead to intellectual disability.

Dr. Quintana agreed that genetic testing will increase, noting an increase in genetic testing ordered from neonatal intensive care units. However, that uptick comes with the caveat of an ever-evolving landscape as genetic companies continue undergoing mergers, acquisitions, and other structural changes that can complicate service availability, provision, and acceptance.

Even if the clinician orders a comprehensive workup, he or she may still encounter resistance at the hands of insurance companies, which can prolong an accurate and prompt diagnosis while hindering families’ access to a thorough investigation.

“Genetic testing is advantageous for insurance companies as well and can prevent unnecessary lab tests to find an answer,” said Dr. Quintana.
 

Accessibility and Lack of Geneticists Often a Rate-Limiting Step

The paucity of geneticists also creates another hurdle. “Where I practice in New Mexico and in many other places in this country, there’s a shortage of geneticists,” Dr. Quintana said. “For 3 years, the state had only one geneticist, and that’s a lot of ground to cover.”

Dr. Quintana went on to stress the importance of neurologists and other clinicians conducting outreach in rural areas despite the logistical barriers; oftentimes, families cannot travel to big cities. Despite these geographical challenges, prenatal genetic testing is becoming more accessible for both rural and urban areas. For that reason, some babies are born with a diagnosis, allowing the parents and healthcare providers to take immediate action.

Moreover, risks and uncertainty exist around genetic testing results and access to long-term life insurance and disability insurance coverage. “Obtaining proper consent prior to genetic testing is very important,” said Dr. Quintana.

In many cases, genetic counseling may be beneficial because it offers patients some additional information and resources that help them understand not only the results of their genetic tests but also the consequences of their conditions.
 

Ultimately, Genetic Testing in Rare Diseases Requires All Stakeholders to Have Patience and Tenacity

Dr. Regier summarized some of the nuances of genetic testing in the rare disease community. “Families understand that you might not be able to make the diagnosis,” Dr. Regier said. “It is more important to them that you stay on the journey with them, even if there is not a diagnosis.”

Another critical element of the diagnostic voyage hinges on clinicians recognizing and honoring that every family ­— and patient — is different.

“Some families want to do testing while others want to take one thing at a time and start with symptom management,” Dr. Regier said. “Both of these approaches are good, and every family has the right to decide when and if genetic testing should be part of their diagnostic odyssey.”

Suggested Reading

Baynam G et al. Stigma Associated With Genetic Testing for Rare Diseases — Causes and Recommendations. Front Genet. 2024 Apr 4:15:1335768. doi: 10.3389/fgene.2024.1335768.

Marwaha S et al. A Guide for the Diagnosis of Rare and Undiagnosed Disease: Beyond the Exome. Genome Med. 2022 Feb 28;14(1):23. doi: 10.1186/s13073-022-01026-w.

The overwhelming majority of rare diseases have a genetic origin, with estimates varying from 71.9% to 80% of rare diseases. Although a rare disease is defined as a condition that affects fewer than 200,000 people domestically, collectively, rare diseases impact approximately 30 million US residents, with at least one of the more than 7,000 rare genetic disorders. In fact, the population of patients with at least one rare disease mirrors the prevalence of people who have type 2 diabetes, or one in every 10 people. Despite their prevalence, most rare conditions are treated only when symptomatic, as many cases remain either misdiagnosed or undiagnosed. As with most health conditions, it is imperative to have a prompt and accurate diagnosis to improve outcomes and avoid inappropriate or unnecessary treatments that may pose severe side effects to the patient.

As the push toward prompt testing and treatment of rare diseases continues building momentum, it has cast a growing spotlight on genetic testing and its potential. To that end, this report weighs the less obvious pros and cons of genetic testing in rare diseases of which neurologists should be aware.
 

The Path to Accurate Diagnosis Remains Long Despite Increased Genetic Testing

When it comes to identifying the greatest challenge in rare genetic disease testing for the neurology community, experts have different opinions. For Kiley Boone Quintana, MD, assistant professor of pediatrics at the University of New Mexico in Albuquerque, the greatest challenge for neurologists navigating this space lies in becoming comfortable with the unknown.

“Many neurologists think genetic testing will certainly find an answer or that the answers will be black and white — which is not true,” said Dr. Quintana. “Instead of clear answers, we often find variants of unknown significance and genetic changes like a deletion or duplication that can have reduced penetrance, so clinicians have to become comfortable with not always having an answer or not knowing exactly how the answer will impact the person.”

Whole Exome and Whole Genome Testing Continues Growing in Prevalence, But Neither Offers a Panacea

Historically, genetic testing was expensive, with only a few genes interrogated at a time. However, the past decade has seen prices simmer down with the introduction of next-generation sequencing — a technology that improves both the accuracy and utility of genetic testing.

One form of genetic testing, called whole exome sequencing, has proven especially helpful in recent years because it looks at all 20,000 genes and spelling changes that can cause mutations and genetic diseases. However, whole exome testing comes with its own limitations. It tests at the DNA loci that produce the actual protein blueprints but does not look at the DNA between those spaces. In addition, the medical community lacks a comprehensive understanding of all 20,000 genes, as scientists have yet to understand all their functions.

Unfortunately, the drawbacks do not stop there.

“Whole exome sequencing is not good at detecting conditions such as Huntington’s disease or Fragile X syndrome,” Dr. Quintana said. “It also fails to pick up spelling changes in DNA of noncoding regions, which we are learning do have functions in epigenetics.”

Quality also can limit reliability of both exome and genome testing. According to Dr. Regier, trustworthiness of results depends on several factors, including the lab conducting the test and the analysis performed. To help ensure quality, Dr. Regier and her colleagues use only CLIA-certified labs and labs that follow the American College of Medical Genetics (ACMG) guidelines. Furthermore, they allow only qualified experts to analyze the results, experts who hold board certifications with either the American College of Medical Genetics and Genomics or the American Board of Pathology.
 

Familial and Societal Stigma Surrounding Rare Diseases Engenders Emotional, Psychological, and Financial Distress

Ultimately, traversing the trajectory of delayed diagnosis and its ambiguity also leaves questions regarding how it will impact the person. All too often, these mysteries transcend the patient with the condition, affecting relatives and other loved ones, as the familial and societal stigma surrounding rare diseases engenders emotional and psychological distress.

In cases with prolonged or delayed diagnostics, Dr. Quintana said that neurologists should advise patients to prepare themselves for the potential of arduous workups — some of which may also come at a high price. Not only does a circuitous path to diagnosis impede treatment initiation, but it often results in major trauma for patients and their caregivers, who encounter significant emotional, psychological, and financial distress in the fallout. Emotional distress of misdiagnosis or lack of a diagnosis remains a significant pain point for patients and their family members alike.

Emotional distress presents the greatest drawback for the rare disease community, according to Dr. Regier. She described the cons of navigating a rare genetic disease diagnosis as “very personal” for families.

“Sometimes, there can be guilt or shame associated with a genetic illness,” Dr. Regier noted. “Understanding the ‘why’ or knowing better how to use nonspecific treatments can be incredibly important to reduce guilt and shame, but it also allows the family to feel like there is a reason and encourages inclusion in the social setting.”

Diagnosis typically results in inclusion in a patient and family group, which increases understanding while easing some of the psychological and emotional stress associated with not knowing the cause.
 

Establishing Social Support Networks Typically Falls on the Patient and Loved Ones

Another con in rare genetic diseases is the lack of adoption across the community.

Because of the long haul, neurologists and other clinicians should recognize the need for patients to have support. Both Dr. Regier and Dr. Quintana agreed that communal support is a critical component of managing the rare genetic disease population. However, finding one’s tribe is easier said than done. Due to the diagnostic hurdles and low number of people with confirmed diagnoses, patient communities and patient advocacy groups for people with individual rare diseases can be underdeveloped. However, the importance of family-based support groups should not be understated. The low community head counts and high level of time investment for care also contributes to poor recruitment turnouts for clinical trials and, subsequently, the sparse number of therapies for such conditions in the pipeline. However, it is also worth noting that, in the case of rare diseases, insufficient disease state knowledge, antiquated policies, lack of funding, and poor research and development diagnostic infrastructure also amplify such cons.

Patients can form communities of support by finding other families and knowing what to expect in terms of complications. While clinicians may not always have the resources to help the patient establish support systems, they can increase the patients’ awareness and encourage them to search for groups that align with their needs. Dr. Quintana reported that many of her patients find support groups of people with the same rare conditions through social media outlets such as Facebook.
 

Lack of Widespread Genetic Testing Adoption Remains a Barrier in Rare Diseases

As Dr. Quintana told Neurology Reviews, geneticists are more likely to order exome testing, despite the fact that genome-wide testing is slightly more likely to find a diagnosis. However, she anticipates that genome-wide testing will gain wider adoption in the future.

In terms of cost and feasibility, genetic testing can identify roughly 50% of the underlying etiology of a rare disease, including phenotyping to make a clinical diagnosis and using genetic testing, according to Dr. Regier.

Regarding the broad use of whole genome sequencing, Dr. Regier foresees that the more we learn about all the diagnostic and prognostic information rare disease testing can give us, “the more this number will grow.”

As an example of the true impact, she shared how new research indicates that changes to one’s DNA can lead to intellectual disability.

Dr. Quintana agreed that genetic testing will increase, noting an increase in genetic testing ordered from neonatal intensive care units. However, that uptick comes with the caveat of an ever-evolving landscape as genetic companies continue undergoing mergers, acquisitions, and other structural changes that can complicate service availability, provision, and acceptance.

Even if the clinician orders a comprehensive workup, he or she may still encounter resistance at the hands of insurance companies, which can prolong an accurate and prompt diagnosis while hindering families’ access to a thorough investigation.

“Genetic testing is advantageous for insurance companies as well and can prevent unnecessary lab tests to find an answer,” said Dr. Quintana.
 

Accessibility and Lack of Geneticists Often a Rate-Limiting Step

The paucity of geneticists also creates another hurdle. “Where I practice in New Mexico and in many other places in this country, there’s a shortage of geneticists,” Dr. Quintana said. “For 3 years, the state had only one geneticist, and that’s a lot of ground to cover.”

Dr. Quintana went on to stress the importance of neurologists and other clinicians conducting outreach in rural areas despite the logistical barriers; oftentimes, families cannot travel to big cities. Despite these geographical challenges, prenatal genetic testing is becoming more accessible for both rural and urban areas. For that reason, some babies are born with a diagnosis, allowing the parents and healthcare providers to take immediate action.

Moreover, risks and uncertainty exist around genetic testing results and access to long-term life insurance and disability insurance coverage. “Obtaining proper consent prior to genetic testing is very important,” said Dr. Quintana.

In many cases, genetic counseling may be beneficial because it offers patients some additional information and resources that help them understand not only the results of their genetic tests but also the consequences of their conditions.
 

Ultimately, Genetic Testing in Rare Diseases Requires All Stakeholders to Have Patience and Tenacity

Dr. Regier summarized some of the nuances of genetic testing in the rare disease community. “Families understand that you might not be able to make the diagnosis,” Dr. Regier said. “It is more important to them that you stay on the journey with them, even if there is not a diagnosis.”

Another critical element of the diagnostic voyage hinges on clinicians recognizing and honoring that every family ­— and patient — is different.

“Some families want to do testing while others want to take one thing at a time and start with symptom management,” Dr. Regier said. “Both of these approaches are good, and every family has the right to decide when and if genetic testing should be part of their diagnostic odyssey.”

Suggested Reading

Baynam G et al. Stigma Associated With Genetic Testing for Rare Diseases — Causes and Recommendations. Front Genet. 2024 Apr 4:15:1335768. doi: 10.3389/fgene.2024.1335768.

Marwaha S et al. A Guide for the Diagnosis of Rare and Undiagnosed Disease: Beyond the Exome. Genome Med. 2022 Feb 28;14(1):23. doi: 10.1186/s13073-022-01026-w.

The overwhelming majority of rare diseases have a genetic origin, with estimates varying from 71.9% to 80% of rare diseases. Although a rare disease is defined as a condition that affects fewer than 200,000 people domestically, collectively, rare diseases impact approximately 30 million US residents, with at least one of the more than 7,000 rare genetic disorders. In fact, the population of patients with at least one rare disease mirrors the prevalence of people who have type 2 diabetes, or one in every 10 people. Despite their prevalence, most rare conditions are treated only when symptomatic, as many cases remain either misdiagnosed or undiagnosed. As with most health conditions, it is imperative to have a prompt and accurate diagnosis to improve outcomes and avoid inappropriate or unnecessary treatments that may pose severe side effects to the patient.

As the push toward prompt testing and treatment of rare diseases continues building momentum, it has cast a growing spotlight on genetic testing and its potential. To that end, this report weighs the less obvious pros and cons of genetic testing in rare diseases of which neurologists should be aware.
 

The Path to Accurate Diagnosis Remains Long Despite Increased Genetic Testing

When it comes to identifying the greatest challenge in rare genetic disease testing for the neurology community, experts have different opinions. For Kiley Boone Quintana, MD, assistant professor of pediatrics at the University of New Mexico in Albuquerque, the greatest challenge for neurologists navigating this space lies in becoming comfortable with the unknown.

“Many neurologists think genetic testing will certainly find an answer or that the answers will be black and white — which is not true,” said Dr. Quintana. “Instead of clear answers, we often find variants of unknown significance and genetic changes like a deletion or duplication that can have reduced penetrance, so clinicians have to become comfortable with not always having an answer or not knowing exactly how the answer will impact the person.”

Whole Exome and Whole Genome Testing Continues Growing in Prevalence, But Neither Offers a Panacea

Historically, genetic testing was expensive, with only a few genes interrogated at a time. However, the past decade has seen prices simmer down with the introduction of next-generation sequencing — a technology that improves both the accuracy and utility of genetic testing.

One form of genetic testing, called whole exome sequencing, has proven especially helpful in recent years because it looks at all 20,000 genes and spelling changes that can cause mutations and genetic diseases. However, whole exome testing comes with its own limitations. It tests at the DNA loci that produce the actual protein blueprints but does not look at the DNA between those spaces. In addition, the medical community lacks a comprehensive understanding of all 20,000 genes, as scientists have yet to understand all their functions.

Unfortunately, the drawbacks do not stop there.

“Whole exome sequencing is not good at detecting conditions such as Huntington’s disease or Fragile X syndrome,” Dr. Quintana said. “It also fails to pick up spelling changes in DNA of noncoding regions, which we are learning do have functions in epigenetics.”

Quality also can limit reliability of both exome and genome testing. According to Dr. Regier, trustworthiness of results depends on several factors, including the lab conducting the test and the analysis performed. To help ensure quality, Dr. Regier and her colleagues use only CLIA-certified labs and labs that follow the American College of Medical Genetics (ACMG) guidelines. Furthermore, they allow only qualified experts to analyze the results, experts who hold board certifications with either the American College of Medical Genetics and Genomics or the American Board of Pathology.
 

Familial and Societal Stigma Surrounding Rare Diseases Engenders Emotional, Psychological, and Financial Distress

Ultimately, traversing the trajectory of delayed diagnosis and its ambiguity also leaves questions regarding how it will impact the person. All too often, these mysteries transcend the patient with the condition, affecting relatives and other loved ones, as the familial and societal stigma surrounding rare diseases engenders emotional and psychological distress.

In cases with prolonged or delayed diagnostics, Dr. Quintana said that neurologists should advise patients to prepare themselves for the potential of arduous workups — some of which may also come at a high price. Not only does a circuitous path to diagnosis impede treatment initiation, but it often results in major trauma for patients and their caregivers, who encounter significant emotional, psychological, and financial distress in the fallout. Emotional distress of misdiagnosis or lack of a diagnosis remains a significant pain point for patients and their family members alike.

Emotional distress presents the greatest drawback for the rare disease community, according to Dr. Regier. She described the cons of navigating a rare genetic disease diagnosis as “very personal” for families.

“Sometimes, there can be guilt or shame associated with a genetic illness,” Dr. Regier noted. “Understanding the ‘why’ or knowing better how to use nonspecific treatments can be incredibly important to reduce guilt and shame, but it also allows the family to feel like there is a reason and encourages inclusion in the social setting.”

Diagnosis typically results in inclusion in a patient and family group, which increases understanding while easing some of the psychological and emotional stress associated with not knowing the cause.
 

Establishing Social Support Networks Typically Falls on the Patient and Loved Ones

Another con in rare genetic diseases is the lack of adoption across the community.

Because of the long haul, neurologists and other clinicians should recognize the need for patients to have support. Both Dr. Regier and Dr. Quintana agreed that communal support is a critical component of managing the rare genetic disease population. However, finding one’s tribe is easier said than done. Due to the diagnostic hurdles and low number of people with confirmed diagnoses, patient communities and patient advocacy groups for people with individual rare diseases can be underdeveloped. However, the importance of family-based support groups should not be understated. The low community head counts and high level of time investment for care also contributes to poor recruitment turnouts for clinical trials and, subsequently, the sparse number of therapies for such conditions in the pipeline. However, it is also worth noting that, in the case of rare diseases, insufficient disease state knowledge, antiquated policies, lack of funding, and poor research and development diagnostic infrastructure also amplify such cons.

Patients can form communities of support by finding other families and knowing what to expect in terms of complications. While clinicians may not always have the resources to help the patient establish support systems, they can increase the patients’ awareness and encourage them to search for groups that align with their needs. Dr. Quintana reported that many of her patients find support groups of people with the same rare conditions through social media outlets such as Facebook.
 

Lack of Widespread Genetic Testing Adoption Remains a Barrier in Rare Diseases

As Dr. Quintana told Neurology Reviews, geneticists are more likely to order exome testing, despite the fact that genome-wide testing is slightly more likely to find a diagnosis. However, she anticipates that genome-wide testing will gain wider adoption in the future.

In terms of cost and feasibility, genetic testing can identify roughly 50% of the underlying etiology of a rare disease, including phenotyping to make a clinical diagnosis and using genetic testing, according to Dr. Regier.

Regarding the broad use of whole genome sequencing, Dr. Regier foresees that the more we learn about all the diagnostic and prognostic information rare disease testing can give us, “the more this number will grow.”

As an example of the true impact, she shared how new research indicates that changes to one’s DNA can lead to intellectual disability.

Dr. Quintana agreed that genetic testing will increase, noting an increase in genetic testing ordered from neonatal intensive care units. However, that uptick comes with the caveat of an ever-evolving landscape as genetic companies continue undergoing mergers, acquisitions, and other structural changes that can complicate service availability, provision, and acceptance.

Even if the clinician orders a comprehensive workup, he or she may still encounter resistance at the hands of insurance companies, which can prolong an accurate and prompt diagnosis while hindering families’ access to a thorough investigation.

“Genetic testing is advantageous for insurance companies as well and can prevent unnecessary lab tests to find an answer,” said Dr. Quintana.
 

Accessibility and Lack of Geneticists Often a Rate-Limiting Step

The paucity of geneticists also creates another hurdle. “Where I practice in New Mexico and in many other places in this country, there’s a shortage of geneticists,” Dr. Quintana said. “For 3 years, the state had only one geneticist, and that’s a lot of ground to cover.”

Dr. Quintana went on to stress the importance of neurologists and other clinicians conducting outreach in rural areas despite the logistical barriers; oftentimes, families cannot travel to big cities. Despite these geographical challenges, prenatal genetic testing is becoming more accessible for both rural and urban areas. For that reason, some babies are born with a diagnosis, allowing the parents and healthcare providers to take immediate action.

Moreover, risks and uncertainty exist around genetic testing results and access to long-term life insurance and disability insurance coverage. “Obtaining proper consent prior to genetic testing is very important,” said Dr. Quintana.

In many cases, genetic counseling may be beneficial because it offers patients some additional information and resources that help them understand not only the results of their genetic tests but also the consequences of their conditions.
 

Ultimately, Genetic Testing in Rare Diseases Requires All Stakeholders to Have Patience and Tenacity

Dr. Regier summarized some of the nuances of genetic testing in the rare disease community. “Families understand that you might not be able to make the diagnosis,” Dr. Regier said. “It is more important to them that you stay on the journey with them, even if there is not a diagnosis.”

Another critical element of the diagnostic voyage hinges on clinicians recognizing and honoring that every family ­— and patient — is different.

“Some families want to do testing while others want to take one thing at a time and start with symptom management,” Dr. Regier said. “Both of these approaches are good, and every family has the right to decide when and if genetic testing should be part of their diagnostic odyssey.”

Suggested Reading

Baynam G et al. Stigma Associated With Genetic Testing for Rare Diseases — Causes and Recommendations. Front Genet. 2024 Apr 4:15:1335768. doi: 10.3389/fgene.2024.1335768.

Marwaha S et al. A Guide for the Diagnosis of Rare and Undiagnosed Disease: Beyond the Exome. Genome Med. 2022 Feb 28;14(1):23. doi: 10.1186/s13073-022-01026-w.