ADHD

The experimental nonstimulant medication viloxazine extended-release, known as SPN-812, reduced symptoms of attention-deficit/hyperactivity disorder (ADHD) as soon as 1 week after dosing and was well tolerated in a randomized, placebo-controlled phase 3 study that included more than 400 children.

mik38/thinkstockphotos.com

In addition to its fast onset of action, the fact that it was effective for both inattentive and hyperactive/impulsive clusters of symptoms is “impressive,” study investigator Andrew Cutler, MD, clinical professor of psychiatry, SUNY Upstate Medical University, Syracuse, N.Y., said in an interviews.

Also noteworthy was the improvement in measures of quality of life and function, “especially function in the areas of school, home life, family relations, and peer relationships, which can be really disrupted with ADHD,” Dr. Cutler said.

The findings were published online July 25 in Clinical Therapeutics.
 

Novel modulating agent

Viloxazine extended-release is a novel multimodal serotonergic and noradrenergic modulating agent with activity at serotonin receptors and the norepinephrine transporter.

The phase 3 randomized controlled trial (RCT) tested the safety and efficacy of two doses of the drug given once daily to children aged 6-11 years with ADHD. About two-thirds were boys.

All participants had an ADHD-Rating Scale–5 (ADHD-RS-5) score of at least 28 and a Clinical Global Impression–Severity score of at least 4. None had taken ADHD medication for at least 1 week prior to randomization.

The intent-to-treat population included 460 children. Of these, 155 were randomly assigned to receive placebo, 147 to receive viloxazine 100 mg, and 158 to receive viloxazine 200 mg.

The primary efficacy endpoint was change from baseline in ADHD-RS-5 total score at week 6. Score changes for both the 100-mg (P = .0004) and the 200-mg (P < .0001) viloxazine groups met statistical significance compared with the placebo group.

Change from baseline in both the ADHD-RS-5 inattention and hyperactivity/impulsivity subscale scores was also significantly reduced in the 100-mg (P = .0006 and .0026, respectively) and 200-mg (P < .0001 and P < .0001, respectively) treatment groups compared with the placebo group.

Improvements occurred after 1 week of treatment and were maintained throughout the 6-week trial, “indicating an early and sustained effect,” the investigators wrote.
 

FDA target action date

The Clinical Global Impression–Improvement (CGI-I) score at 6 weeks was significantly improved in those receiving 100 mg (P = .0020) and 200 mg (P < .0001) of the active treatment compared with placebo.

The CGI-I responder rate, the percentage of children with a CGI-I score of 1 (very much improved) or 2 (much improved), was significantly higher at 6 weeks with viloxazine 100 mg and 200 mg vs. placebo (45% and 51% vs. 30%, respectively; P = .0065 and P = .0002).

These standard investigator-rated assessments were supported by two parent self-rated assessments: the Conners 3–Parent Short Form and the Weiss Functional Impairment Rating Scale–Parent Form.

Parents noted improvement not only in their children’s ADHD symptoms but also in ADHD-associated learning problems, executive functioning, defiance/aggression, peer relations, and functioning in different settings.

At both doses, once-daily viloxazine was generally well tolerated, with a low rate of discontinuation because of adverse events (<5%). Most adverse events were characterized as mild or moderate in severity and included somnolence (8.9%), decreased appetite (6.0%), and headache (5.4%).

On the basis of results of this study and others, the Food and Drug Administration accepted the company’s new drug application for viloxazine extended-release for ADHD in children and adolescents. The application has a target action date of Nov. 8, 2020.
 

Potential advantages

Commenting on the study in an interview, Dean Elbe, PharmD, clinical pharmacy specialist, child and adolescent mental health, BC Children’s Hospital, Vancouver, B.C., said that use of viloxazine to treat ADHD is “interesting.”

Dr. Elbe, who was not involved with the current research, noted that “it is actually an old drug that has been around since the mid-1970s in Europe as an antidepressant. It was removed from the market due to poor sales, not safety issues.”

Overall, on the basis of this study, viloxazine has potential to offer “modest improvements” over atomoxetine (Strattera), and the dosing may be “more straightforward and somewhat less challenging than with atomoxetine, with no taper up and no adjustment for poor 2D6 metabolizers,” Dr. Elbe noted.

“The onset of action appears somewhat quicker than we typically see with atomoxetine, so that is also helpful for parent and clinician acceptance and partially overcomes a perceived barrier with atomoxetine,” he said.

Dr. Elbe said he wonders, however, whether viloxazine will show “real-world clinical utility for both hyperactive-impulsive as well as inattentive symptoms. Although the study shows efficacy in both symptom clusters, so did the atomoxetine RCTs, and this has not been the clinical impression for atomoxetine.”

The study was funded by Supernus Pharmaceuticals. Dr. Cutler is a consultant for Supernus, as well as for Adlon Therapeutics, Aevi Genomics, Akili Interactive, Arbor Pharmaceuticals, Ironshore, KemPharm, Lundbeck, Neos Therapeutics, NLS Pharma, Otsuka, Purdue, Shire, Sunovion, Takeda, and Tris Pharma. He has received speaker/promotional honoraria from Adlon Therapeutics, Arbor Pharmaceuticals, Lundbeck, Neos Therapeutics, Otsuka, Shire, Sunovion, Takeda, and Tris Pharma and has received research grants from Aevi Genomics, Akili Interactive, Arbor Pharmaceuticals, Ironshore, KemPharm, Lundbeck, Neos Therapeutics, Otsuka, Purdue, Shire, Sunovion, Supernus Pharmaceuticals, Takeda, and Tris Pharma. A complete list of disclosures for the other authors is available in the original article. Dr. Elbe has reported no relevant financial relationships.
 

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

The experimental nonstimulant medication viloxazine extended-release, known as SPN-812, reduced symptoms of attention-deficit/hyperactivity disorder (ADHD) as soon as 1 week after dosing and was well tolerated in a randomized, placebo-controlled phase 3 study that included more than 400 children.

mik38/thinkstockphotos.com

In addition to its fast onset of action, the fact that it was effective for both inattentive and hyperactive/impulsive clusters of symptoms is “impressive,” study investigator Andrew Cutler, MD, clinical professor of psychiatry, SUNY Upstate Medical University, Syracuse, N.Y., said in an interviews.

Also noteworthy was the improvement in measures of quality of life and function, “especially function in the areas of school, home life, family relations, and peer relationships, which can be really disrupted with ADHD,” Dr. Cutler said.

The findings were published online July 25 in Clinical Therapeutics.
 

Novel modulating agent

Viloxazine extended-release is a novel multimodal serotonergic and noradrenergic modulating agent with activity at serotonin receptors and the norepinephrine transporter.

The phase 3 randomized controlled trial (RCT) tested the safety and efficacy of two doses of the drug given once daily to children aged 6-11 years with ADHD. About two-thirds were boys.

All participants had an ADHD-Rating Scale–5 (ADHD-RS-5) score of at least 28 and a Clinical Global Impression–Severity score of at least 4. None had taken ADHD medication for at least 1 week prior to randomization.

The intent-to-treat population included 460 children. Of these, 155 were randomly assigned to receive placebo, 147 to receive viloxazine 100 mg, and 158 to receive viloxazine 200 mg.

The primary efficacy endpoint was change from baseline in ADHD-RS-5 total score at week 6. Score changes for both the 100-mg (P = .0004) and the 200-mg (P < .0001) viloxazine groups met statistical significance compared with the placebo group.

Change from baseline in both the ADHD-RS-5 inattention and hyperactivity/impulsivity subscale scores was also significantly reduced in the 100-mg (P = .0006 and .0026, respectively) and 200-mg (P < .0001 and P < .0001, respectively) treatment groups compared with the placebo group.

Improvements occurred after 1 week of treatment and were maintained throughout the 6-week trial, “indicating an early and sustained effect,” the investigators wrote.
 

FDA target action date

The Clinical Global Impression–Improvement (CGI-I) score at 6 weeks was significantly improved in those receiving 100 mg (P = .0020) and 200 mg (P < .0001) of the active treatment compared with placebo.

The CGI-I responder rate, the percentage of children with a CGI-I score of 1 (very much improved) or 2 (much improved), was significantly higher at 6 weeks with viloxazine 100 mg and 200 mg vs. placebo (45% and 51% vs. 30%, respectively; P = .0065 and P = .0002).

These standard investigator-rated assessments were supported by two parent self-rated assessments: the Conners 3–Parent Short Form and the Weiss Functional Impairment Rating Scale–Parent Form.

Parents noted improvement not only in their children’s ADHD symptoms but also in ADHD-associated learning problems, executive functioning, defiance/aggression, peer relations, and functioning in different settings.

At both doses, once-daily viloxazine was generally well tolerated, with a low rate of discontinuation because of adverse events (<5%). Most adverse events were characterized as mild or moderate in severity and included somnolence (8.9%), decreased appetite (6.0%), and headache (5.4%).

On the basis of results of this study and others, the Food and Drug Administration accepted the company’s new drug application for viloxazine extended-release for ADHD in children and adolescents. The application has a target action date of Nov. 8, 2020.
 

Potential advantages

Commenting on the study in an interview, Dean Elbe, PharmD, clinical pharmacy specialist, child and adolescent mental health, BC Children’s Hospital, Vancouver, B.C., said that use of viloxazine to treat ADHD is “interesting.”

Dr. Elbe, who was not involved with the current research, noted that “it is actually an old drug that has been around since the mid-1970s in Europe as an antidepressant. It was removed from the market due to poor sales, not safety issues.”

Overall, on the basis of this study, viloxazine has potential to offer “modest improvements” over atomoxetine (Strattera), and the dosing may be “more straightforward and somewhat less challenging than with atomoxetine, with no taper up and no adjustment for poor 2D6 metabolizers,” Dr. Elbe noted.

“The onset of action appears somewhat quicker than we typically see with atomoxetine, so that is also helpful for parent and clinician acceptance and partially overcomes a perceived barrier with atomoxetine,” he said.

Dr. Elbe said he wonders, however, whether viloxazine will show “real-world clinical utility for both hyperactive-impulsive as well as inattentive symptoms. Although the study shows efficacy in both symptom clusters, so did the atomoxetine RCTs, and this has not been the clinical impression for atomoxetine.”

The study was funded by Supernus Pharmaceuticals. Dr. Cutler is a consultant for Supernus, as well as for Adlon Therapeutics, Aevi Genomics, Akili Interactive, Arbor Pharmaceuticals, Ironshore, KemPharm, Lundbeck, Neos Therapeutics, NLS Pharma, Otsuka, Purdue, Shire, Sunovion, Takeda, and Tris Pharma. He has received speaker/promotional honoraria from Adlon Therapeutics, Arbor Pharmaceuticals, Lundbeck, Neos Therapeutics, Otsuka, Shire, Sunovion, Takeda, and Tris Pharma and has received research grants from Aevi Genomics, Akili Interactive, Arbor Pharmaceuticals, Ironshore, KemPharm, Lundbeck, Neos Therapeutics, Otsuka, Purdue, Shire, Sunovion, Supernus Pharmaceuticals, Takeda, and Tris Pharma. A complete list of disclosures for the other authors is available in the original article. Dr. Elbe has reported no relevant financial relationships.
 

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

The experimental nonstimulant medication viloxazine extended-release, known as SPN-812, reduced symptoms of attention-deficit/hyperactivity disorder (ADHD) as soon as 1 week after dosing and was well tolerated in a randomized, placebo-controlled phase 3 study that included more than 400 children.

mik38/thinkstockphotos.com

In addition to its fast onset of action, the fact that it was effective for both inattentive and hyperactive/impulsive clusters of symptoms is “impressive,” study investigator Andrew Cutler, MD, clinical professor of psychiatry, SUNY Upstate Medical University, Syracuse, N.Y., said in an interviews.

Also noteworthy was the improvement in measures of quality of life and function, “especially function in the areas of school, home life, family relations, and peer relationships, which can be really disrupted with ADHD,” Dr. Cutler said.

The findings were published online July 25 in Clinical Therapeutics.
 

Novel modulating agent

Viloxazine extended-release is a novel multimodal serotonergic and noradrenergic modulating agent with activity at serotonin receptors and the norepinephrine transporter.

The phase 3 randomized controlled trial (RCT) tested the safety and efficacy of two doses of the drug given once daily to children aged 6-11 years with ADHD. About two-thirds were boys.

All participants had an ADHD-Rating Scale–5 (ADHD-RS-5) score of at least 28 and a Clinical Global Impression–Severity score of at least 4. None had taken ADHD medication for at least 1 week prior to randomization.

The intent-to-treat population included 460 children. Of these, 155 were randomly assigned to receive placebo, 147 to receive viloxazine 100 mg, and 158 to receive viloxazine 200 mg.

The primary efficacy endpoint was change from baseline in ADHD-RS-5 total score at week 6. Score changes for both the 100-mg (P = .0004) and the 200-mg (P < .0001) viloxazine groups met statistical significance compared with the placebo group.

Change from baseline in both the ADHD-RS-5 inattention and hyperactivity/impulsivity subscale scores was also significantly reduced in the 100-mg (P = .0006 and .0026, respectively) and 200-mg (P < .0001 and P < .0001, respectively) treatment groups compared with the placebo group.

Improvements occurred after 1 week of treatment and were maintained throughout the 6-week trial, “indicating an early and sustained effect,” the investigators wrote.
 

FDA target action date

The Clinical Global Impression–Improvement (CGI-I) score at 6 weeks was significantly improved in those receiving 100 mg (P = .0020) and 200 mg (P < .0001) of the active treatment compared with placebo.

The CGI-I responder rate, the percentage of children with a CGI-I score of 1 (very much improved) or 2 (much improved), was significantly higher at 6 weeks with viloxazine 100 mg and 200 mg vs. placebo (45% and 51% vs. 30%, respectively; P = .0065 and P = .0002).

These standard investigator-rated assessments were supported by two parent self-rated assessments: the Conners 3–Parent Short Form and the Weiss Functional Impairment Rating Scale–Parent Form.

Parents noted improvement not only in their children’s ADHD symptoms but also in ADHD-associated learning problems, executive functioning, defiance/aggression, peer relations, and functioning in different settings.

At both doses, once-daily viloxazine was generally well tolerated, with a low rate of discontinuation because of adverse events (<5%). Most adverse events were characterized as mild or moderate in severity and included somnolence (8.9%), decreased appetite (6.0%), and headache (5.4%).

On the basis of results of this study and others, the Food and Drug Administration accepted the company’s new drug application for viloxazine extended-release for ADHD in children and adolescents. The application has a target action date of Nov. 8, 2020.
 

Potential advantages

Commenting on the study in an interview, Dean Elbe, PharmD, clinical pharmacy specialist, child and adolescent mental health, BC Children’s Hospital, Vancouver, B.C., said that use of viloxazine to treat ADHD is “interesting.”

Dr. Elbe, who was not involved with the current research, noted that “it is actually an old drug that has been around since the mid-1970s in Europe as an antidepressant. It was removed from the market due to poor sales, not safety issues.”

Overall, on the basis of this study, viloxazine has potential to offer “modest improvements” over atomoxetine (Strattera), and the dosing may be “more straightforward and somewhat less challenging than with atomoxetine, with no taper up and no adjustment for poor 2D6 metabolizers,” Dr. Elbe noted.

“The onset of action appears somewhat quicker than we typically see with atomoxetine, so that is also helpful for parent and clinician acceptance and partially overcomes a perceived barrier with atomoxetine,” he said.

Dr. Elbe said he wonders, however, whether viloxazine will show “real-world clinical utility for both hyperactive-impulsive as well as inattentive symptoms. Although the study shows efficacy in both symptom clusters, so did the atomoxetine RCTs, and this has not been the clinical impression for atomoxetine.”

The study was funded by Supernus Pharmaceuticals. Dr. Cutler is a consultant for Supernus, as well as for Adlon Therapeutics, Aevi Genomics, Akili Interactive, Arbor Pharmaceuticals, Ironshore, KemPharm, Lundbeck, Neos Therapeutics, NLS Pharma, Otsuka, Purdue, Shire, Sunovion, Takeda, and Tris Pharma. He has received speaker/promotional honoraria from Adlon Therapeutics, Arbor Pharmaceuticals, Lundbeck, Neos Therapeutics, Otsuka, Shire, Sunovion, Takeda, and Tris Pharma and has received research grants from Aevi Genomics, Akili Interactive, Arbor Pharmaceuticals, Ironshore, KemPharm, Lundbeck, Neos Therapeutics, Otsuka, Purdue, Shire, Sunovion, Supernus Pharmaceuticals, Takeda, and Tris Pharma. A complete list of disclosures for the other authors is available in the original article. Dr. Elbe has reported no relevant financial relationships.
 

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

The novel lysine-specific demethylase 1 inhibitor vafidemstat (ORY-2001, Oryzon Genomics) is effective for treating agitation and aggression across a number of psychiatric disorders, new research suggests.

The REIMAGINE trial included 30 patients with autism spectrum disorder (ASD), ADHD, or borderline personality disorder (BPD). Results showed significant improvements after 8 weeks in general functioning and agitation-aggression scores for all three disorders.

The study “supports vafidemstat as an emerging therapeutic option to treat aggression-agitation, as well as the nonaggression features of psychiatric diseases with high unmet medical need,” lead researcher Roger Bullock, MD, Oryzon Genomics, Corneliá De Llobregat, Spain, told Medscape Medical News.

“This is the first clinical demonstration of an epigenetic mode of action in psychiatry to date,” Bullock added.

However, another expert urged prudence when interpreting the findings.

“The study results must be viewed with caution, given the inherent limitations of an open-label trial, small sample size, and weak rationale for the sample selection,” said Nathan Kolla, MD, PhD, a psychiatrist at the University of Toronto, Canada, who was not involved with the research.

The findings were presented at the European Psychiatric Association (EPA) 2020 Congress, which was held online this year because of the COVID-19 pandemic.
 

Little evidence available

“Epigenetic mechanisms have been proposed in many psychiatric conditions, but so far, little clinical evidence is available,” Bullock said during his presentation.

In preclinical models, vafidemstat has been associated with a reduction in aggressive behavior “and the normal response to stress of immediate early genes in the prefrontal cortex” via the modification of gene transcription, noted Bullock.

“This new approach makes it a good candidate to look at aggression in multiple psychiatric and CNS conditions,” he added.

REIMAGINE was a phase 2a open-label trial that included 30 patients (53% women; mean age, 33.5 years; 87% White) with psychiatric disorders who had significant or persistent agitation or aggression that was disruptive of the patients› daily life.

Among the participants, 12 had BPD, 11 had ADHD, and seven had ASD. All were treated with vafidemstat 1.2 mg for 8 weeks.

In all, 23 patients completed all 8 weeks of treatment, including nine patients with BPD, eight with ADHD, and six with ASD.

Results showed that the study drug was well tolerated, with no serious adverse events reported and no patients withdrawing because of safety-related events.

The most common adverse events were headache (20%) and insomnia (10%), which resolved without intervention or treatment modification.
 

Significantly improved scores

Across the whole cohort, the drug was associated with significant reductions in scores over baseline on the Clinical Global Impression–Severity (CGI-S) and CGI-Improvement (CGI-I) scales. There were also significant improvements for Neuropsychiatric Inventory (NPI) total scores and agitation-aggression scores (P < .001 for comparisons).

Similar results were observed with respect to individual diagnoses, albeit at varying degrees of significance for each scale.

Patients with BPD experienced significant reductions in scores on the Borderline Personality Disorder Checklist (BPDCL) (P < .01). Patients with ADHD experienced reductions on the ADHD Rating Scale (P < .05).

Patients with BPD also experienced reductions in suicidal ideation, as measured with the Columbia Suicide Severity Rating Scale (P < .01). That is “the only cohort where this trait is relevant,” the researchers note.

In addition, significant correlations were shown between NPI total scores and scores on the BPDCL after treatment with vafidemstat (P = .015), as well as between NPI agitation-aggression scores and both CGI-I (P = .008) and CGI-S scores (P = .0001).

“This convergence of signals in scales of different nature and scope support the pharmacological role of vafidemstat in controlling aggression-agitation in different psychiatric conditions,” the investigators note.

Bullock added that further randomized placebo-controlled clinical trials “to confirm vafidemstat’s potential to treat aggression-agitation in psychiatric disorders are now planned.”

First up will be PORTICO, which is planned to start over the coming months in Spain and will include patients with BPD.
 

Several limitations

Commenting on the study for Medscape Medical News, Kolla, who is also a researcher at the Center for Addiction and Mental Health, noted that REIMAGINE was originally designed to test vafidemstat for the treatment of agitation and aggression in patients with Alzheimer’s disease (AD).

“It seems peculiar that the study investigators would choose to examine three additional psychiatric disorders that bear little resemblance to AD in terms of phenomenology. Additionally, the etiological underpinnings of the three disorders likely differ markedly from AD,” said Kolla, who was not involved with the research.

In addition, the “very small” sample size in each group makes it difficult to interpret the investigators’ conclusions, he noted.

There are also “many more sophisticated scales” to assess agitation and aggression than what were used in the study, he added.

Kolla also questioned the notion that a drug such as vafidemstat satisfies an unmet clinical need for the treatment of aggression and agitation.

Trials that “purport to reduce aggression in these populations often provide some level of global improvement in functioning that may appear as if they directly treat agitation or aggression,” he said. “However, no drug has ever been developed that directly reduces aggression and agitation.”

That means that, for now, there is insufficient evidence to “conclude that vafidemstat overcomes the unmet medical need of treating aggression/agitation,” he said.

For Kolla, the concept of a psychiatric drug that works by effecting epigenetic changes to the genome is also questionable, although such mechanisms may “play a role in the salubrious effects of certain mood stabilizers or antipsychotics for which better-defined mechanisms of action have been established.”

The study was funded by Oryzon Genomics. Bullock and the other investigators are employees of Oryzon Genomics.

This article first appeared on Medscape.com.

The novel lysine-specific demethylase 1 inhibitor vafidemstat (ORY-2001, Oryzon Genomics) is effective for treating agitation and aggression across a number of psychiatric disorders, new research suggests.

The REIMAGINE trial included 30 patients with autism spectrum disorder (ASD), ADHD, or borderline personality disorder (BPD). Results showed significant improvements after 8 weeks in general functioning and agitation-aggression scores for all three disorders.

The study “supports vafidemstat as an emerging therapeutic option to treat aggression-agitation, as well as the nonaggression features of psychiatric diseases with high unmet medical need,” lead researcher Roger Bullock, MD, Oryzon Genomics, Corneliá De Llobregat, Spain, told Medscape Medical News.

“This is the first clinical demonstration of an epigenetic mode of action in psychiatry to date,” Bullock added.

However, another expert urged prudence when interpreting the findings.

“The study results must be viewed with caution, given the inherent limitations of an open-label trial, small sample size, and weak rationale for the sample selection,” said Nathan Kolla, MD, PhD, a psychiatrist at the University of Toronto, Canada, who was not involved with the research.

The findings were presented at the European Psychiatric Association (EPA) 2020 Congress, which was held online this year because of the COVID-19 pandemic.
 

Little evidence available

“Epigenetic mechanisms have been proposed in many psychiatric conditions, but so far, little clinical evidence is available,” Bullock said during his presentation.

In preclinical models, vafidemstat has been associated with a reduction in aggressive behavior “and the normal response to stress of immediate early genes in the prefrontal cortex” via the modification of gene transcription, noted Bullock.

“This new approach makes it a good candidate to look at aggression in multiple psychiatric and CNS conditions,” he added.

REIMAGINE was a phase 2a open-label trial that included 30 patients (53% women; mean age, 33.5 years; 87% White) with psychiatric disorders who had significant or persistent agitation or aggression that was disruptive of the patients› daily life.

Among the participants, 12 had BPD, 11 had ADHD, and seven had ASD. All were treated with vafidemstat 1.2 mg for 8 weeks.

In all, 23 patients completed all 8 weeks of treatment, including nine patients with BPD, eight with ADHD, and six with ASD.

Results showed that the study drug was well tolerated, with no serious adverse events reported and no patients withdrawing because of safety-related events.

The most common adverse events were headache (20%) and insomnia (10%), which resolved without intervention or treatment modification.
 

Significantly improved scores

Across the whole cohort, the drug was associated with significant reductions in scores over baseline on the Clinical Global Impression–Severity (CGI-S) and CGI-Improvement (CGI-I) scales. There were also significant improvements for Neuropsychiatric Inventory (NPI) total scores and agitation-aggression scores (P < .001 for comparisons).

Similar results were observed with respect to individual diagnoses, albeit at varying degrees of significance for each scale.

Patients with BPD experienced significant reductions in scores on the Borderline Personality Disorder Checklist (BPDCL) (P < .01). Patients with ADHD experienced reductions on the ADHD Rating Scale (P < .05).

Patients with BPD also experienced reductions in suicidal ideation, as measured with the Columbia Suicide Severity Rating Scale (P < .01). That is “the only cohort where this trait is relevant,” the researchers note.

In addition, significant correlations were shown between NPI total scores and scores on the BPDCL after treatment with vafidemstat (P = .015), as well as between NPI agitation-aggression scores and both CGI-I (P = .008) and CGI-S scores (P = .0001).

“This convergence of signals in scales of different nature and scope support the pharmacological role of vafidemstat in controlling aggression-agitation in different psychiatric conditions,” the investigators note.

Bullock added that further randomized placebo-controlled clinical trials “to confirm vafidemstat’s potential to treat aggression-agitation in psychiatric disorders are now planned.”

First up will be PORTICO, which is planned to start over the coming months in Spain and will include patients with BPD.
 

Several limitations

Commenting on the study for Medscape Medical News, Kolla, who is also a researcher at the Center for Addiction and Mental Health, noted that REIMAGINE was originally designed to test vafidemstat for the treatment of agitation and aggression in patients with Alzheimer’s disease (AD).

“It seems peculiar that the study investigators would choose to examine three additional psychiatric disorders that bear little resemblance to AD in terms of phenomenology. Additionally, the etiological underpinnings of the three disorders likely differ markedly from AD,” said Kolla, who was not involved with the research.

In addition, the “very small” sample size in each group makes it difficult to interpret the investigators’ conclusions, he noted.

There are also “many more sophisticated scales” to assess agitation and aggression than what were used in the study, he added.

Kolla also questioned the notion that a drug such as vafidemstat satisfies an unmet clinical need for the treatment of aggression and agitation.

Trials that “purport to reduce aggression in these populations often provide some level of global improvement in functioning that may appear as if they directly treat agitation or aggression,” he said. “However, no drug has ever been developed that directly reduces aggression and agitation.”

That means that, for now, there is insufficient evidence to “conclude that vafidemstat overcomes the unmet medical need of treating aggression/agitation,” he said.

For Kolla, the concept of a psychiatric drug that works by effecting epigenetic changes to the genome is also questionable, although such mechanisms may “play a role in the salubrious effects of certain mood stabilizers or antipsychotics for which better-defined mechanisms of action have been established.”

The study was funded by Oryzon Genomics. Bullock and the other investigators are employees of Oryzon Genomics.

This article first appeared on Medscape.com.

The novel lysine-specific demethylase 1 inhibitor vafidemstat (ORY-2001, Oryzon Genomics) is effective for treating agitation and aggression across a number of psychiatric disorders, new research suggests.

The REIMAGINE trial included 30 patients with autism spectrum disorder (ASD), ADHD, or borderline personality disorder (BPD). Results showed significant improvements after 8 weeks in general functioning and agitation-aggression scores for all three disorders.

The study “supports vafidemstat as an emerging therapeutic option to treat aggression-agitation, as well as the nonaggression features of psychiatric diseases with high unmet medical need,” lead researcher Roger Bullock, MD, Oryzon Genomics, Corneliá De Llobregat, Spain, told Medscape Medical News.

“This is the first clinical demonstration of an epigenetic mode of action in psychiatry to date,” Bullock added.

However, another expert urged prudence when interpreting the findings.

“The study results must be viewed with caution, given the inherent limitations of an open-label trial, small sample size, and weak rationale for the sample selection,” said Nathan Kolla, MD, PhD, a psychiatrist at the University of Toronto, Canada, who was not involved with the research.

The findings were presented at the European Psychiatric Association (EPA) 2020 Congress, which was held online this year because of the COVID-19 pandemic.
 

Little evidence available

“Epigenetic mechanisms have been proposed in many psychiatric conditions, but so far, little clinical evidence is available,” Bullock said during his presentation.

In preclinical models, vafidemstat has been associated with a reduction in aggressive behavior “and the normal response to stress of immediate early genes in the prefrontal cortex” via the modification of gene transcription, noted Bullock.

“This new approach makes it a good candidate to look at aggression in multiple psychiatric and CNS conditions,” he added.

REIMAGINE was a phase 2a open-label trial that included 30 patients (53% women; mean age, 33.5 years; 87% White) with psychiatric disorders who had significant or persistent agitation or aggression that was disruptive of the patients› daily life.

Among the participants, 12 had BPD, 11 had ADHD, and seven had ASD. All were treated with vafidemstat 1.2 mg for 8 weeks.

In all, 23 patients completed all 8 weeks of treatment, including nine patients with BPD, eight with ADHD, and six with ASD.

Results showed that the study drug was well tolerated, with no serious adverse events reported and no patients withdrawing because of safety-related events.

The most common adverse events were headache (20%) and insomnia (10%), which resolved without intervention or treatment modification.
 

Significantly improved scores

Across the whole cohort, the drug was associated with significant reductions in scores over baseline on the Clinical Global Impression–Severity (CGI-S) and CGI-Improvement (CGI-I) scales. There were also significant improvements for Neuropsychiatric Inventory (NPI) total scores and agitation-aggression scores (P < .001 for comparisons).

Similar results were observed with respect to individual diagnoses, albeit at varying degrees of significance for each scale.

Patients with BPD experienced significant reductions in scores on the Borderline Personality Disorder Checklist (BPDCL) (P < .01). Patients with ADHD experienced reductions on the ADHD Rating Scale (P < .05).

Patients with BPD also experienced reductions in suicidal ideation, as measured with the Columbia Suicide Severity Rating Scale (P < .01). That is “the only cohort where this trait is relevant,” the researchers note.

In addition, significant correlations were shown between NPI total scores and scores on the BPDCL after treatment with vafidemstat (P = .015), as well as between NPI agitation-aggression scores and both CGI-I (P = .008) and CGI-S scores (P = .0001).

“This convergence of signals in scales of different nature and scope support the pharmacological role of vafidemstat in controlling aggression-agitation in different psychiatric conditions,” the investigators note.

Bullock added that further randomized placebo-controlled clinical trials “to confirm vafidemstat’s potential to treat aggression-agitation in psychiatric disorders are now planned.”

First up will be PORTICO, which is planned to start over the coming months in Spain and will include patients with BPD.
 

Several limitations

Commenting on the study for Medscape Medical News, Kolla, who is also a researcher at the Center for Addiction and Mental Health, noted that REIMAGINE was originally designed to test vafidemstat for the treatment of agitation and aggression in patients with Alzheimer’s disease (AD).

“It seems peculiar that the study investigators would choose to examine three additional psychiatric disorders that bear little resemblance to AD in terms of phenomenology. Additionally, the etiological underpinnings of the three disorders likely differ markedly from AD,” said Kolla, who was not involved with the research.

In addition, the “very small” sample size in each group makes it difficult to interpret the investigators’ conclusions, he noted.

There are also “many more sophisticated scales” to assess agitation and aggression than what were used in the study, he added.

Kolla also questioned the notion that a drug such as vafidemstat satisfies an unmet clinical need for the treatment of aggression and agitation.

Trials that “purport to reduce aggression in these populations often provide some level of global improvement in functioning that may appear as if they directly treat agitation or aggression,” he said. “However, no drug has ever been developed that directly reduces aggression and agitation.”

That means that, for now, there is insufficient evidence to “conclude that vafidemstat overcomes the unmet medical need of treating aggression/agitation,” he said.

For Kolla, the concept of a psychiatric drug that works by effecting epigenetic changes to the genome is also questionable, although such mechanisms may “play a role in the salubrious effects of certain mood stabilizers or antipsychotics for which better-defined mechanisms of action have been established.”

The study was funded by Oryzon Genomics. Bullock and the other investigators are employees of Oryzon Genomics.

This article first appeared on Medscape.com.

Functional MRI-based intersubject correlations (ISCs) hold promise for studying the neural bases of ADHD’s heterogeneous symptoms in situations that reflect real-world difficulties, new research shows.

“The present results provide the first evidence of a connection between symptom scales and brain activity recorded when the participants have been involved in a situation that is similar to the ones where their difficulties typically occur,” wrote Juha Salmi, of the department of neuroscience and biomedical engineering at Aalto University in Espoo, Finland, and associates. The study was published in NeuroImage.

Many imaging studies in ADHD are too narrow and fail to reflect real-world situations and distractions, the investigators wrote. For the current study, the investigators conducted fMRI scans of participants in “cocktail party” situations. During fMRI, the participants viewed excerpts from the 2008 Finnish film “Three Wise Men,” in which three men were talking.

“There were periods when no additional distractors were presented and periods when the film was embedded with irrelevant distractors that the participants were told to ignore. The three different distractors (white noise, green; jazz music, red; speech, magenta) and nondistracted periods (blue) were presented in a pseudo-randomized order so that all other distractor types had to occur before the same distractor type was presented again,” the authors wrote. Each distractor lasted for 15 seconds.

The ISC approach sought to gauge how much neural networks in each group, 51 with ADHD and 29 without, “ticked together” – that is, synchronized and coordinated in a feature-specific manner.

As expected, across the film, ISCs of those in the ADHD group were weaker than were those in the control group in multiple brain areas, including the left precuneus, bilateral medial occipital cortices, left lateral occipital cortex, left temporoparietal junction, and medial and posterior parts of the left superior temporal cortex. Likewise, when the other distractors occurred – with the exception of constant white noise – weaker ISCs were found among the ADHD group. In fact, there were no brain regions in which healthy controls had weaker ISCs than did those with ADHD.

“Our results demonstrate the ISCs computed from the naturalistic neuroimaging data contain rich information about the variability of individual brain responses,” the investigators wrote. “At least theoretically, this approach could be used to identify neural patterns reflecting specific symptoms in complex, dynamic situations.”

One limitation of naturalistic studies is that the inferences are by their nature more general than they might be in more conventional, discrete experiments. Bridging the gap between naturalistic studies such as this one and other more conventional designs are needed, the investigators wrote, because dove-tailing their findings could provide significant insights.

The study was supported by the Academy of Finland and the Åbo Akademi University Endowment for the BrainTrain project. None of the authors have any biomedical financial interests or potential conflicts of interest.

cpalmer@mdedge.com

SOURCE: Salmi J et al. Neuroimage. 2019 Nov 12. doi: 10.1016/j.neuroimage.2019.116352.

Functional MRI-based intersubject correlations (ISCs) hold promise for studying the neural bases of ADHD’s heterogeneous symptoms in situations that reflect real-world difficulties, new research shows.

“The present results provide the first evidence of a connection between symptom scales and brain activity recorded when the participants have been involved in a situation that is similar to the ones where their difficulties typically occur,” wrote Juha Salmi, of the department of neuroscience and biomedical engineering at Aalto University in Espoo, Finland, and associates. The study was published in NeuroImage.

Many imaging studies in ADHD are too narrow and fail to reflect real-world situations and distractions, the investigators wrote. For the current study, the investigators conducted fMRI scans of participants in “cocktail party” situations. During fMRI, the participants viewed excerpts from the 2008 Finnish film “Three Wise Men,” in which three men were talking.

“There were periods when no additional distractors were presented and periods when the film was embedded with irrelevant distractors that the participants were told to ignore. The three different distractors (white noise, green; jazz music, red; speech, magenta) and nondistracted periods (blue) were presented in a pseudo-randomized order so that all other distractor types had to occur before the same distractor type was presented again,” the authors wrote. Each distractor lasted for 15 seconds.

The ISC approach sought to gauge how much neural networks in each group, 51 with ADHD and 29 without, “ticked together” – that is, synchronized and coordinated in a feature-specific manner.

As expected, across the film, ISCs of those in the ADHD group were weaker than were those in the control group in multiple brain areas, including the left precuneus, bilateral medial occipital cortices, left lateral occipital cortex, left temporoparietal junction, and medial and posterior parts of the left superior temporal cortex. Likewise, when the other distractors occurred – with the exception of constant white noise – weaker ISCs were found among the ADHD group. In fact, there were no brain regions in which healthy controls had weaker ISCs than did those with ADHD.

“Our results demonstrate the ISCs computed from the naturalistic neuroimaging data contain rich information about the variability of individual brain responses,” the investigators wrote. “At least theoretically, this approach could be used to identify neural patterns reflecting specific symptoms in complex, dynamic situations.”

One limitation of naturalistic studies is that the inferences are by their nature more general than they might be in more conventional, discrete experiments. Bridging the gap between naturalistic studies such as this one and other more conventional designs are needed, the investigators wrote, because dove-tailing their findings could provide significant insights.

The study was supported by the Academy of Finland and the Åbo Akademi University Endowment for the BrainTrain project. None of the authors have any biomedical financial interests or potential conflicts of interest.

cpalmer@mdedge.com

SOURCE: Salmi J et al. Neuroimage. 2019 Nov 12. doi: 10.1016/j.neuroimage.2019.116352.

Functional MRI-based intersubject correlations (ISCs) hold promise for studying the neural bases of ADHD’s heterogeneous symptoms in situations that reflect real-world difficulties, new research shows.

“The present results provide the first evidence of a connection between symptom scales and brain activity recorded when the participants have been involved in a situation that is similar to the ones where their difficulties typically occur,” wrote Juha Salmi, of the department of neuroscience and biomedical engineering at Aalto University in Espoo, Finland, and associates. The study was published in NeuroImage.

Many imaging studies in ADHD are too narrow and fail to reflect real-world situations and distractions, the investigators wrote. For the current study, the investigators conducted fMRI scans of participants in “cocktail party” situations. During fMRI, the participants viewed excerpts from the 2008 Finnish film “Three Wise Men,” in which three men were talking.

“There were periods when no additional distractors were presented and periods when the film was embedded with irrelevant distractors that the participants were told to ignore. The three different distractors (white noise, green; jazz music, red; speech, magenta) and nondistracted periods (blue) were presented in a pseudo-randomized order so that all other distractor types had to occur before the same distractor type was presented again,” the authors wrote. Each distractor lasted for 15 seconds.

The ISC approach sought to gauge how much neural networks in each group, 51 with ADHD and 29 without, “ticked together” – that is, synchronized and coordinated in a feature-specific manner.

As expected, across the film, ISCs of those in the ADHD group were weaker than were those in the control group in multiple brain areas, including the left precuneus, bilateral medial occipital cortices, left lateral occipital cortex, left temporoparietal junction, and medial and posterior parts of the left superior temporal cortex. Likewise, when the other distractors occurred – with the exception of constant white noise – weaker ISCs were found among the ADHD group. In fact, there were no brain regions in which healthy controls had weaker ISCs than did those with ADHD.

“Our results demonstrate the ISCs computed from the naturalistic neuroimaging data contain rich information about the variability of individual brain responses,” the investigators wrote. “At least theoretically, this approach could be used to identify neural patterns reflecting specific symptoms in complex, dynamic situations.”

One limitation of naturalistic studies is that the inferences are by their nature more general than they might be in more conventional, discrete experiments. Bridging the gap between naturalistic studies such as this one and other more conventional designs are needed, the investigators wrote, because dove-tailing their findings could provide significant insights.

The study was supported by the Academy of Finland and the Åbo Akademi University Endowment for the BrainTrain project. None of the authors have any biomedical financial interests or potential conflicts of interest.

cpalmer@mdedge.com

SOURCE: Salmi J et al. Neuroimage. 2019 Nov 12. doi: 10.1016/j.neuroimage.2019.116352.

The day wouldn’t be so bad if he would just go to sleep at night! How many times have you heard this plea from parents of your patients with ADHD? Sleep is important for everyone, but getting enough is both more important and more difficult for children with ADHD. About three-quarters of children with ADHD have significant problems with sleep, most even before any medication treatment. And inadequate sleep can exacerbate or even cause ADHD symptoms!

SeventyFour/iStock/Getty Images

Solving sleep problems for children with ADHD is not always simple. The kinds of sleep issues that are more common in children (and adults) with ADHD, compared with typical children, include behavioral bedtime resistance, circadian rhythm sleep disorder (CRSD), insomnia, morning sleepiness, night waking, periodic limb movement disorder (PLMD), restless leg syndrome (RLS), and sleep disordered breathing (SDB). Such a broad differential means a careful history and sometimes even lab studies may be needed.

Both initial and follow-up visits for ADHD should include a sleep history or, ideally, a tool such as BEARS sleep screening tool or Children’s Sleep Habits Questionnaire and a 2-week sleep diary (http://www.sleepfoundation.org/). These are good ways to collect signs of allergies or apnea (for SDB), limb movements or limb pain (for RLS or PLMD), mouth breathing, night waking, and snoring.

You also need to ask about alcohol, drugs, caffeine, and nicotine; asthma; comorbid conditions such as mental health disorders or their treatments; and enuresis (alone or part of nocturnal seizures).

Do I need to remind you to find out about electronics activating the child before bedtime – hidden under the covers, or signaling messages from friends in the middle of the night – and to encourage limits on these? Some sleep disorders warrant polysomnography in a sleep lab or from MyZeo.com (for PLMD and some SDB) or ferritin less than 50 mg/L (for RLS) for diagnosis and to guide treatment. Nasal steroids, antihistamines, or montelukast may help SDB when there are enlarged tonsils or adenoids, but adenotonsillectomy is usually curative.

The first line and most effective treatment for sleep problems in children with or without ADHD is improving sleep hygiene. Improved sleep “hygiene” sounds easy, but for children with ADHD and their parents, who often have ADHD too, changing behaviors can be tough! The key component is establishing habits for the entire sleep cycle: a steady pattern of reduced stimulation in the hour before bedtime (sans electronics); a friendly rather than irritated bedtime routine; and the same bedtime and wake up time, ideally 7 days per week. Bedtime stories read to the child can soothe at any age, not just toddlers! Of course, both children and families want fun and special occasions. For most, varying bedtime by up to 1 hour won’t mess up their biological clock, but for some even this should be avoided. Sleeping alone in a cool, dark, quiet room, nightly in the same bed (not used for other activities), is considered the ideal. Earplugs, white noise generators, and eye masks may be helpful. If sleeping with siblings is a necessity, bedtimes can be staggered to put the child to bed earlier or after others are asleep.

Struggles postponing bedtime may be part of a pattern of oppositionality common in ADHD, but the child may not be tired due to being off schedule (from CRSD), napping on the bus or after school, sleeping in mornings, or unrealistic parent expectations for sleep duration. Parents may want their hyperactive children to give them a break and go to bed at 8 p.m., but children aged 6-10 years need only 10-11 hours and those aged 10-17 years need 8.5-9.25 hours of sleep.

Not tired may instead be “wired” from lingering stimulant effects or even lack of such medication leaving the child overactive or rebounding from earlier medications. Lower afternoon doses or shorter-acting medication may solve lasting medication issues, but sometimes an additional low dose of stimulants actually will help a child with ADHD settle at bedtime. All stimulant medications can prolong sleep onset, often by 30 minutes, but this varies by individual and tends to resolve on its own a few weeks after a new or changed medicine. Switching medication category may allow a child to fall asleep faster. Atomoxetine and alpha agonists are less likely to delay sleep than methylphenidate (MPH).

What if sleep hygiene, behavioral methods, and adjusting ADHD medications is not enough? If sleep issues are causing significant problems, medication for sleep is worth a try. Controlled-release melatonin 1-2 hours before bedtime has data for effectiveness. There is no defined dose, so the lowest effective dose should be used, but 3-6 mg may be needed. Because many families with a child with ADHD are not organized enough to give medicine on this schedule, sublingual melatonin that acts in 15-20 minutes is a good alternative or even first choice. Clonidine 0.05-0.2 mg 1 hour before bedtime speeds sleep onset, lasts 3 hours, and does not carry over to sedation the next day. Stronger psychopharmaceuticals can assist sleep onset, including low dose mirtazapine or trazodone, but have the side effect of daytime sleepiness.

Management of waking in the middle of the night can be more difficult to treat as sleep drive has been dissipated. First, consider whether trips out of bed reflect a sleep association that has not been extinguished. Daytime atomoxetine or, better yet, MPH may improve night waking, and sometimes even a low-dose evening, long-acting medication, such as osmotic release oral system (OROS) extended release methylphenidate HCL (OROS MPH), helps. Short-acting clonidine or melatonin in the middle of the night or bedtime mirtazapine or trazodone also may be worth a try.

When dealing with sleep, keep in mind that 50% or more of children with ADHD have a coexisting mental health disorder. Anxiety, separation anxiety, depression, and dysthymia all often affect sleep onset, night waking, and sometimes early morning waking. The child or teen may need extra reassurance or company at bedtime (siblings or pets may suffice). Reading positive stories or playing soft music may be better at setting a positive mood and sense of safety for sleep, certainly more so than social media, which should be avoided.

Keep in mind that substance use is more common in ADHD as well as with those other mental health conditions and can interfere with restful sleep and make RLS worse. Bipolar disorder can be mistaken for ADHD as it often presents with hyperactivity but also can be comorbid. Sleep problems are increased sixfold when both are present. Prolonged periods awake at night and diminished need for sleep are signs that help differentiate bipolar from ADHD. Medication management for the bipolar disorder with atypicals can reduce sleep latency and reduce REM sleep, but also causes morning fatigue. Medications to treat other mental health problems can help sleep onset (for example, anticonvulsants, atypicals), or prolong it (SSRIs), change REM states (atypicals), and even exacerbate RLS (SSRIs). You can make changes or work with the child’s mental health specialist if medications are causing significant sleep problems.

When we help improve sleep for children with ADHD, it can lessen not only ADHD symptoms but also some symptoms of other mental health disorders, improve learning and behavior, and greatly improve family quality of life!
 

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at pdnews@mdedge.com.

The day wouldn’t be so bad if he would just go to sleep at night! How many times have you heard this plea from parents of your patients with ADHD? Sleep is important for everyone, but getting enough is both more important and more difficult for children with ADHD. About three-quarters of children with ADHD have significant problems with sleep, most even before any medication treatment. And inadequate sleep can exacerbate or even cause ADHD symptoms!

SeventyFour/iStock/Getty Images

Solving sleep problems for children with ADHD is not always simple. The kinds of sleep issues that are more common in children (and adults) with ADHD, compared with typical children, include behavioral bedtime resistance, circadian rhythm sleep disorder (CRSD), insomnia, morning sleepiness, night waking, periodic limb movement disorder (PLMD), restless leg syndrome (RLS), and sleep disordered breathing (SDB). Such a broad differential means a careful history and sometimes even lab studies may be needed.

Both initial and follow-up visits for ADHD should include a sleep history or, ideally, a tool such as BEARS sleep screening tool or Children’s Sleep Habits Questionnaire and a 2-week sleep diary (http://www.sleepfoundation.org/). These are good ways to collect signs of allergies or apnea (for SDB), limb movements or limb pain (for RLS or PLMD), mouth breathing, night waking, and snoring.

You also need to ask about alcohol, drugs, caffeine, and nicotine; asthma; comorbid conditions such as mental health disorders or their treatments; and enuresis (alone or part of nocturnal seizures).

Do I need to remind you to find out about electronics activating the child before bedtime – hidden under the covers, or signaling messages from friends in the middle of the night – and to encourage limits on these? Some sleep disorders warrant polysomnography in a sleep lab or from MyZeo.com (for PLMD and some SDB) or ferritin less than 50 mg/L (for RLS) for diagnosis and to guide treatment. Nasal steroids, antihistamines, or montelukast may help SDB when there are enlarged tonsils or adenoids, but adenotonsillectomy is usually curative.

The first line and most effective treatment for sleep problems in children with or without ADHD is improving sleep hygiene. Improved sleep “hygiene” sounds easy, but for children with ADHD and their parents, who often have ADHD too, changing behaviors can be tough! The key component is establishing habits for the entire sleep cycle: a steady pattern of reduced stimulation in the hour before bedtime (sans electronics); a friendly rather than irritated bedtime routine; and the same bedtime and wake up time, ideally 7 days per week. Bedtime stories read to the child can soothe at any age, not just toddlers! Of course, both children and families want fun and special occasions. For most, varying bedtime by up to 1 hour won’t mess up their biological clock, but for some even this should be avoided. Sleeping alone in a cool, dark, quiet room, nightly in the same bed (not used for other activities), is considered the ideal. Earplugs, white noise generators, and eye masks may be helpful. If sleeping with siblings is a necessity, bedtimes can be staggered to put the child to bed earlier or after others are asleep.

Struggles postponing bedtime may be part of a pattern of oppositionality common in ADHD, but the child may not be tired due to being off schedule (from CRSD), napping on the bus or after school, sleeping in mornings, or unrealistic parent expectations for sleep duration. Parents may want their hyperactive children to give them a break and go to bed at 8 p.m., but children aged 6-10 years need only 10-11 hours and those aged 10-17 years need 8.5-9.25 hours of sleep.

Not tired may instead be “wired” from lingering stimulant effects or even lack of such medication leaving the child overactive or rebounding from earlier medications. Lower afternoon doses or shorter-acting medication may solve lasting medication issues, but sometimes an additional low dose of stimulants actually will help a child with ADHD settle at bedtime. All stimulant medications can prolong sleep onset, often by 30 minutes, but this varies by individual and tends to resolve on its own a few weeks after a new or changed medicine. Switching medication category may allow a child to fall asleep faster. Atomoxetine and alpha agonists are less likely to delay sleep than methylphenidate (MPH).

What if sleep hygiene, behavioral methods, and adjusting ADHD medications is not enough? If sleep issues are causing significant problems, medication for sleep is worth a try. Controlled-release melatonin 1-2 hours before bedtime has data for effectiveness. There is no defined dose, so the lowest effective dose should be used, but 3-6 mg may be needed. Because many families with a child with ADHD are not organized enough to give medicine on this schedule, sublingual melatonin that acts in 15-20 minutes is a good alternative or even first choice. Clonidine 0.05-0.2 mg 1 hour before bedtime speeds sleep onset, lasts 3 hours, and does not carry over to sedation the next day. Stronger psychopharmaceuticals can assist sleep onset, including low dose mirtazapine or trazodone, but have the side effect of daytime sleepiness.

Management of waking in the middle of the night can be more difficult to treat as sleep drive has been dissipated. First, consider whether trips out of bed reflect a sleep association that has not been extinguished. Daytime atomoxetine or, better yet, MPH may improve night waking, and sometimes even a low-dose evening, long-acting medication, such as osmotic release oral system (OROS) extended release methylphenidate HCL (OROS MPH), helps. Short-acting clonidine or melatonin in the middle of the night or bedtime mirtazapine or trazodone also may be worth a try.

When dealing with sleep, keep in mind that 50% or more of children with ADHD have a coexisting mental health disorder. Anxiety, separation anxiety, depression, and dysthymia all often affect sleep onset, night waking, and sometimes early morning waking. The child or teen may need extra reassurance or company at bedtime (siblings or pets may suffice). Reading positive stories or playing soft music may be better at setting a positive mood and sense of safety for sleep, certainly more so than social media, which should be avoided.

Keep in mind that substance use is more common in ADHD as well as with those other mental health conditions and can interfere with restful sleep and make RLS worse. Bipolar disorder can be mistaken for ADHD as it often presents with hyperactivity but also can be comorbid. Sleep problems are increased sixfold when both are present. Prolonged periods awake at night and diminished need for sleep are signs that help differentiate bipolar from ADHD. Medication management for the bipolar disorder with atypicals can reduce sleep latency and reduce REM sleep, but also causes morning fatigue. Medications to treat other mental health problems can help sleep onset (for example, anticonvulsants, atypicals), or prolong it (SSRIs), change REM states (atypicals), and even exacerbate RLS (SSRIs). You can make changes or work with the child’s mental health specialist if medications are causing significant sleep problems.

When we help improve sleep for children with ADHD, it can lessen not only ADHD symptoms but also some symptoms of other mental health disorders, improve learning and behavior, and greatly improve family quality of life!
 

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at pdnews@mdedge.com.

The day wouldn’t be so bad if he would just go to sleep at night! How many times have you heard this plea from parents of your patients with ADHD? Sleep is important for everyone, but getting enough is both more important and more difficult for children with ADHD. About three-quarters of children with ADHD have significant problems with sleep, most even before any medication treatment. And inadequate sleep can exacerbate or even cause ADHD symptoms!

SeventyFour/iStock/Getty Images

Solving sleep problems for children with ADHD is not always simple. The kinds of sleep issues that are more common in children (and adults) with ADHD, compared with typical children, include behavioral bedtime resistance, circadian rhythm sleep disorder (CRSD), insomnia, morning sleepiness, night waking, periodic limb movement disorder (PLMD), restless leg syndrome (RLS), and sleep disordered breathing (SDB). Such a broad differential means a careful history and sometimes even lab studies may be needed.

Both initial and follow-up visits for ADHD should include a sleep history or, ideally, a tool such as BEARS sleep screening tool or Children’s Sleep Habits Questionnaire and a 2-week sleep diary (http://www.sleepfoundation.org/). These are good ways to collect signs of allergies or apnea (for SDB), limb movements or limb pain (for RLS or PLMD), mouth breathing, night waking, and snoring.

You also need to ask about alcohol, drugs, caffeine, and nicotine; asthma; comorbid conditions such as mental health disorders or their treatments; and enuresis (alone or part of nocturnal seizures).

Do I need to remind you to find out about electronics activating the child before bedtime – hidden under the covers, or signaling messages from friends in the middle of the night – and to encourage limits on these? Some sleep disorders warrant polysomnography in a sleep lab or from MyZeo.com (for PLMD and some SDB) or ferritin less than 50 mg/L (for RLS) for diagnosis and to guide treatment. Nasal steroids, antihistamines, or montelukast may help SDB when there are enlarged tonsils or adenoids, but adenotonsillectomy is usually curative.

The first line and most effective treatment for sleep problems in children with or without ADHD is improving sleep hygiene. Improved sleep “hygiene” sounds easy, but for children with ADHD and their parents, who often have ADHD too, changing behaviors can be tough! The key component is establishing habits for the entire sleep cycle: a steady pattern of reduced stimulation in the hour before bedtime (sans electronics); a friendly rather than irritated bedtime routine; and the same bedtime and wake up time, ideally 7 days per week. Bedtime stories read to the child can soothe at any age, not just toddlers! Of course, both children and families want fun and special occasions. For most, varying bedtime by up to 1 hour won’t mess up their biological clock, but for some even this should be avoided. Sleeping alone in a cool, dark, quiet room, nightly in the same bed (not used for other activities), is considered the ideal. Earplugs, white noise generators, and eye masks may be helpful. If sleeping with siblings is a necessity, bedtimes can be staggered to put the child to bed earlier or after others are asleep.

Struggles postponing bedtime may be part of a pattern of oppositionality common in ADHD, but the child may not be tired due to being off schedule (from CRSD), napping on the bus or after school, sleeping in mornings, or unrealistic parent expectations for sleep duration. Parents may want their hyperactive children to give them a break and go to bed at 8 p.m., but children aged 6-10 years need only 10-11 hours and those aged 10-17 years need 8.5-9.25 hours of sleep.

Not tired may instead be “wired” from lingering stimulant effects or even lack of such medication leaving the child overactive or rebounding from earlier medications. Lower afternoon doses or shorter-acting medication may solve lasting medication issues, but sometimes an additional low dose of stimulants actually will help a child with ADHD settle at bedtime. All stimulant medications can prolong sleep onset, often by 30 minutes, but this varies by individual and tends to resolve on its own a few weeks after a new or changed medicine. Switching medication category may allow a child to fall asleep faster. Atomoxetine and alpha agonists are less likely to delay sleep than methylphenidate (MPH).

What if sleep hygiene, behavioral methods, and adjusting ADHD medications is not enough? If sleep issues are causing significant problems, medication for sleep is worth a try. Controlled-release melatonin 1-2 hours before bedtime has data for effectiveness. There is no defined dose, so the lowest effective dose should be used, but 3-6 mg may be needed. Because many families with a child with ADHD are not organized enough to give medicine on this schedule, sublingual melatonin that acts in 15-20 minutes is a good alternative or even first choice. Clonidine 0.05-0.2 mg 1 hour before bedtime speeds sleep onset, lasts 3 hours, and does not carry over to sedation the next day. Stronger psychopharmaceuticals can assist sleep onset, including low dose mirtazapine or trazodone, but have the side effect of daytime sleepiness.

Management of waking in the middle of the night can be more difficult to treat as sleep drive has been dissipated. First, consider whether trips out of bed reflect a sleep association that has not been extinguished. Daytime atomoxetine or, better yet, MPH may improve night waking, and sometimes even a low-dose evening, long-acting medication, such as osmotic release oral system (OROS) extended release methylphenidate HCL (OROS MPH), helps. Short-acting clonidine or melatonin in the middle of the night or bedtime mirtazapine or trazodone also may be worth a try.

When dealing with sleep, keep in mind that 50% or more of children with ADHD have a coexisting mental health disorder. Anxiety, separation anxiety, depression, and dysthymia all often affect sleep onset, night waking, and sometimes early morning waking. The child or teen may need extra reassurance or company at bedtime (siblings or pets may suffice). Reading positive stories or playing soft music may be better at setting a positive mood and sense of safety for sleep, certainly more so than social media, which should be avoided.

Keep in mind that substance use is more common in ADHD as well as with those other mental health conditions and can interfere with restful sleep and make RLS worse. Bipolar disorder can be mistaken for ADHD as it often presents with hyperactivity but also can be comorbid. Sleep problems are increased sixfold when both are present. Prolonged periods awake at night and diminished need for sleep are signs that help differentiate bipolar from ADHD. Medication management for the bipolar disorder with atypicals can reduce sleep latency and reduce REM sleep, but also causes morning fatigue. Medications to treat other mental health problems can help sleep onset (for example, anticonvulsants, atypicals), or prolong it (SSRIs), change REM states (atypicals), and even exacerbate RLS (SSRIs). You can make changes or work with the child’s mental health specialist if medications are causing significant sleep problems.

When we help improve sleep for children with ADHD, it can lessen not only ADHD symptoms but also some symptoms of other mental health disorders, improve learning and behavior, and greatly improve family quality of life!
 

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at pdnews@mdedge.com.

Social anxiety is more likely in adolescents aged 12-18 years with predominantly inattentive ADHD and psychiatric comorbidities, according to María Jesús Mardomingo-Sanz, MD, PhD, and associates.

A total of 234 ADHD patients with a mean age of 14.9 years were recruited for the cross-sectional, observational study, and social anxiety was assessed using the Social Anxiety Scale for Adolescents (SAS-A). Just under 70% were male; 37.2% had predominantly inattentive disease, 9% had predominantly hyperactive-impulsive disease, and 51.7% had combined-type disease. Nearly all patients received pharmacologic therapy: 78.6% received methylphenidate, 15% received lisdexamfetamine, and 4.3% received atomoxetine, reported Dr. Mardomingo-Sanz, of the child psychiatry and psychology section at the Hospital General Universitario Gregorio Marañón in Madrid, and associates. The study was published in Anales de Pediatría.

The investigators found that 50.4% of patients had a psychiatric comorbidity. Learning and communication disorders, and anxiety disorders were the most common, occurring in 20.1% and 19.2% of all patients, respectively. Patients within the cohort scored significantly higher on the SAS-A, compared with reference values in a healthy population.

Patients with predominantly inattentive disease had significantly higher scores in the SAS-A, compared with those with predominantly hyperactive-impulsive disease (P = .015). Comorbid anxiety disorder was associated with the worst SAS-A scores (P less than .001).

“Social anxiety greatly influences the way in which children and adolescents interact with the surrounding environment and react to it, and therefore can contribute to the development of psychiatric comorbidities. Social anxiety detected by the SAS-A questionnaire is not diagnostic of an anxiety disorder, but detecting it is important, as it can contribute to the secondary prevention of future comorbidities that could lead to less favorable outcomes of these stage of development in patients with ADHD,” the investigators concluded.

Laboratorios Farmacéuticos funded the study, and the investigators reported receiving fees and being employed by Laboratorios Farmacéuticos.

lfranki@mdedge.com

SOURCE: Mardomingo-Sanz MJ et al. An Pediatr (Barc). 2019;90(6):349-61.

Social anxiety is more likely in adolescents aged 12-18 years with predominantly inattentive ADHD and psychiatric comorbidities, according to María Jesús Mardomingo-Sanz, MD, PhD, and associates.

A total of 234 ADHD patients with a mean age of 14.9 years were recruited for the cross-sectional, observational study, and social anxiety was assessed using the Social Anxiety Scale for Adolescents (SAS-A). Just under 70% were male; 37.2% had predominantly inattentive disease, 9% had predominantly hyperactive-impulsive disease, and 51.7% had combined-type disease. Nearly all patients received pharmacologic therapy: 78.6% received methylphenidate, 15% received lisdexamfetamine, and 4.3% received atomoxetine, reported Dr. Mardomingo-Sanz, of the child psychiatry and psychology section at the Hospital General Universitario Gregorio Marañón in Madrid, and associates. The study was published in Anales de Pediatría.

The investigators found that 50.4% of patients had a psychiatric comorbidity. Learning and communication disorders, and anxiety disorders were the most common, occurring in 20.1% and 19.2% of all patients, respectively. Patients within the cohort scored significantly higher on the SAS-A, compared with reference values in a healthy population.

Patients with predominantly inattentive disease had significantly higher scores in the SAS-A, compared with those with predominantly hyperactive-impulsive disease (P = .015). Comorbid anxiety disorder was associated with the worst SAS-A scores (P less than .001).

“Social anxiety greatly influences the way in which children and adolescents interact with the surrounding environment and react to it, and therefore can contribute to the development of psychiatric comorbidities. Social anxiety detected by the SAS-A questionnaire is not diagnostic of an anxiety disorder, but detecting it is important, as it can contribute to the secondary prevention of future comorbidities that could lead to less favorable outcomes of these stage of development in patients with ADHD,” the investigators concluded.

Laboratorios Farmacéuticos funded the study, and the investigators reported receiving fees and being employed by Laboratorios Farmacéuticos.

lfranki@mdedge.com

SOURCE: Mardomingo-Sanz MJ et al. An Pediatr (Barc). 2019;90(6):349-61.

Social anxiety is more likely in adolescents aged 12-18 years with predominantly inattentive ADHD and psychiatric comorbidities, according to María Jesús Mardomingo-Sanz, MD, PhD, and associates.

A total of 234 ADHD patients with a mean age of 14.9 years were recruited for the cross-sectional, observational study, and social anxiety was assessed using the Social Anxiety Scale for Adolescents (SAS-A). Just under 70% were male; 37.2% had predominantly inattentive disease, 9% had predominantly hyperactive-impulsive disease, and 51.7% had combined-type disease. Nearly all patients received pharmacologic therapy: 78.6% received methylphenidate, 15% received lisdexamfetamine, and 4.3% received atomoxetine, reported Dr. Mardomingo-Sanz, of the child psychiatry and psychology section at the Hospital General Universitario Gregorio Marañón in Madrid, and associates. The study was published in Anales de Pediatría.

The investigators found that 50.4% of patients had a psychiatric comorbidity. Learning and communication disorders, and anxiety disorders were the most common, occurring in 20.1% and 19.2% of all patients, respectively. Patients within the cohort scored significantly higher on the SAS-A, compared with reference values in a healthy population.

Patients with predominantly inattentive disease had significantly higher scores in the SAS-A, compared with those with predominantly hyperactive-impulsive disease (P = .015). Comorbid anxiety disorder was associated with the worst SAS-A scores (P less than .001).

“Social anxiety greatly influences the way in which children and adolescents interact with the surrounding environment and react to it, and therefore can contribute to the development of psychiatric comorbidities. Social anxiety detected by the SAS-A questionnaire is not diagnostic of an anxiety disorder, but detecting it is important, as it can contribute to the secondary prevention of future comorbidities that could lead to less favorable outcomes of these stage of development in patients with ADHD,” the investigators concluded.

Laboratorios Farmacéuticos funded the study, and the investigators reported receiving fees and being employed by Laboratorios Farmacéuticos.

lfranki@mdedge.com

SOURCE: Mardomingo-Sanz MJ et al. An Pediatr (Barc). 2019;90(6):349-61.

CASE Disruptive and inattentive

R, age 9, is brought by his mother to our child/adolescent psychiatry clinic, where he has been receiving treatment for attention-deficit/hyperactivity disorder (ADHD), because he is experiencing visual hallucinations and exhibiting aggressive behavior. R had initially been prescribed (and had been taking) short-acting methylphenidate, 5 mg every morning for weeks. During this time, he responded well to the medication; he had reduced hyperactivity, talked less in class, and was able to give increased attention to his academic work. After 2 weeks, because R did not want to take short-acting methylphenidate in school, we switched him to osmotic-controlled release oral delivery system (OROS) methylphenidate, 18 mg every morning.

Two days after starting the OROS methyl­phenidate formulation, R develops visual hallucinations and aggressive behavior. His visual hallucinations—which occur both at home and at school—involve seeing snakes circling him. When hallucinating, he hits and pushes family members and throws objects at them. He refuses to go to school because he fears the snakes. The hallucinations continue throughout the day and persist for the next 3 to 4 days.

R does not have any comorbid medical or psychiatric illnesses; however, his father has a history of schizophrenia, polysubstance abuse, and multiple prior psychiatric hospitalizations due to medication noncompliance.

R undergoes laboratory workup, which includes a complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone level, and urine drug screening. All results are within normal limits.

[polldaddy:10468215]

The authors’ observations

We ruled out delirium by ordering a basic laboratory workup. We considered the possibility of a new mood or psychotic disorder, but began to suspect the OROS methylphenidate might be causing R’s symptoms.

Attention-deficit/hyperactivity disorder is an increasingly prevalent diagnosis in the United States, affecting up to 6.4 million children age 4 to 17. While symptoms of ADHD often first appear in preschool-age children, the average age at which a child receives a diagnosis of ADHD is 7.

Stimulants are a clinically effective treatment for ADHD. In general, their use is safe and well tolerated, especially in pediatric patients. Some common adverse effects of stimulant medications include reduced appetite, headache, and insomnia.¹ Psychotic symptoms such as paranoid delusions, visual hallucinations, auditory hallucinations, and tactile hallucinations are rare. In some cases, these psychotic symptoms can be accompanied by increased aggression.^2-4

Continue to: Methylphenidate is one of the most...

Methylphenidate is one of the most commonly prescribed stimulants for treating ADHD. Methylphenidate has 2 known mechanisms of action: 1) inhibition of catecholamine reuptake at the presynaptic dopamine reuptake inhibitor, and 2) binding to and blocking intracellular dopamine transporters, inhibiting both dopamine and norepinephrine reuptake.^5,6 Because increased levels of synaptic dopamine are implicated in the generation of psychotic symptoms, the pharmacologic mechanism of methylphenidate also implies a potential to induce psychotic symptoms.⁷

How common is this problem?

On the population level, there is no detectable difference in the event rate (incidence) of psychosis in children treated with stimulants or children not taking stimulants.⁸ However, there are reports that individual patients can experience psychosis due to treatment with stimulants as an unusual adverse medication reaction. In 1971, Lucas and Weiss⁹ were among the first to describe 3 cases of methylphenidate-induced psychosis. Since then, many articles in the scientific literature have reported cases of psychosis related to stimulant medications.

A brief review of the literature between 2002 and 2010 revealed 14 cases of stimulant-related psychosis, in patients ranging from age 7 to 45. Six of the patients were children, age 7 to 12; 1 patient was an adolescent, age 15; 4 were young adults, age 18 to 25; and 3 were older adults. Of all 14 individuals, 7 reported visual hallucinations, 4 had tactile hallucinations, 4 had auditory hallucinations, and 3 displayed paranoid delusions.¹⁰ With the aim of exploring possible etiologic factors associated with psychotic symptoms, such as type of drug and dosage, it was found that 9 patients received methylphenidate, with total daily doses ranging from 7.5 to 74 mg (3 patients received short-acting methylphenidate; 1 patient received methylphenidate extended release (ER); 1 patient received both; 4 patients received dextroamphetamine, with doses of 30 to 50 mg/d; and 1 patient received amphetamine, 10 mg/d). In terms of family history, 1 patient had a positive family history of schizophrenia; 1 patient had a family history of bipolar disorder; and 6 patients were negative for family history of any psychotic disorder.¹⁰

In 2006, due to growing concerns about adverse psychiatric effects of ADHD medications, the FDA Center for Drug Evaluation and Research Office of Surveillance and Epidemiology requested the electronic clinical trial databases of manufacturers of drugs approved for the treatment of ADHD, or those with active clinical development programs for the same indication.¹¹ In that study, Mosholder et al¹¹ analyzed data from 49 randomized, controlled clinical trials that were in pediatric development programs and found that there were psychotic or manic adverse events in 11 individuals in the pooled active drug group. These were observed with methylphenidate, dexmethylphenidate, and atomoxetine. There were no events in the placebo group, which reinforced the causality between the ADHD medication and these symptoms, as participants with untreated ADHD did not develop them.¹¹

It is important to note that ADHD medications taken in excessive doses are much more likely to provoke psychotic adverse effects than when taken at therapeutic doses. However, as seen in our clinical case, patients such as R could develop acute psychosis even with a lower dosage of stimulant medications. An article by Ross² suggested rates of .25% for this psychiatric adverse effect (1 in 400 children treated with therapeutic doses of stimulants will develop psychosis), which is consistent with the data from the Mosholder et al¹¹ study.

Continue to: TREATMENT Discontinuation and re-challenge

After 3 days, we discontinue OROS methylphenidate. Five days after discontinuation, R’s visual hallucinations and aggressive behaviors completely resolve. After not receiving stimulants for 2 weeks, R is restarted on short-acting methylphenidate, 5 mg/d, because he had a relatively good clinical response to short-acting methylphenidate previously. After 14 days, the short-acting methylphenidate dosage is increased to 5 mg twice daily without the re-emergence of psychosis or aggressive behaviors.

The authors’ observations

Although stimulant-induced psychosis can be a disturbing adverse effect, severe ADHD greatly affects a person’s functioning at school and at home and can lead to several comorbidities, including depression, anxiety, and substance abuse. For these reasons, most patients with ADHD who experience psychotic symptoms are re-challenged with stimulants.¹⁰ Out of the 14 cases discussed above, 4 patients were restarted on the same stimulant or a different ADHD medication; 2 of them had the same psychotic symptoms days after the reintroduction of the drug and the other 2 had no recurrence.^10,12,13

Stimulant-induced hallucinations

The emergence of hallucinations with methylphenidate or amphetamines has been attributed to a chronic increase of dopamine levels in the synaptic cleft, while the pathophysiological mechanisms are not clearly known. In some cases, hallucinations emerged after taking the first low dose, which has been thought to be an effect of idiosyncratic mechanism. Stimulants cause an increase of the releasing of catecholamines. Porfirio et al¹⁴ argue that high-dose stimulants can deteriorate the response to visual stimuli, causing a different perception of visual stimuli in susceptible children, based on the information that norepinephrine is released in the lateral geniculate nucleus, and it increases the transmission of visual information.

An idiosyncratic drug reaction

Despite the existence of many theories on the pathophysiology of stimulant-induced psychosis (Box^15-18), its actual mechanism remains unknown. In R’s case, given the speed with which his symptoms developed, the proposed mechanisms of action may not explain his psychotic symptoms. We must consider an idiosyncratic drug reaction as an explanation. This suggestion is supported by the fact that re-challenging with a stimulant did not re-induce psychosis in 2 out of the 4 cases described in the literature,^10,12,13 as well as in R’s case.

Box

Although the mechanisms by which psychotic symptoms associated with stimulants occur remain unknown, possibilities include^10,19:

• genetic predisposition
• changes induced by stimulants at the level of neurotransmitters, synapses, and brain circuits
• an idiosyncratic drug reaction.

Continue to: What to consider before prescribing stimulants

While stimulants are clearly beneficial for the vast majority of children with ADHD, there may be a small subgroup of patients for whom stimulants carry increased risk. For example, it is possible that patients with a family history of mood and psychotic disorders may be more vulnerable to stimulant-induced psychotic symptoms that are reversible on discontinuation.²⁰ In our case, R had a first-degree relative (his father) with treatment-refractory schizophrenia.

Attentional dysfunction is a common premorbid presentation for children who later develop schizophrenia or bipolar disorder. Retrospective data from patients with schizophrenia or bipolar disorder document high rates of childhood stimulant use—generally higher even than other groups with attentional dysfunction²¹ and histories of stimulant-associated adverse behavioral effects.²² In these patients, a history of stimulant use is also associated with an earlier age at onset²³ and a more severe course of illness during hospitalization.²⁴ Stimulant exposure in vulnerable individuals may hasten the onset or worsen the course of bipolar or psychotic illnesses.^21,25,26

OUTCOME Well-controlled symptoms

R continues to receive short-acting methylphenidate, 5 mg twice a day. His ADHD symptoms remain well-controlled, and he is able to do well academically.

The authors’ observations

Although stimulant-induced psychosis is a rare and unpredictable occurrence, carefully monitoring all patients for any adverse effects of ADHD medication is recommended. When present, psychotic symptoms may quickly remit upon discontinuation of the medication. The question of subsequently reintroducing stimulant medication for a patient with severe ADHD is complicated. One needs to measure the possible risk of a reoccurrence of the psychotic symptoms against the consequences of untreated ADHD. These consequences include increased risk for academic and occupational failure, depression, anxiety, and substance abuse. Psychosocial interventions for ADHD should be implemented, but for optimal results, they often need to be combined with medication. However, if a stimulant medication is to be reintroduced, this should be done with extreme care. Starting dosages need to be low, and increases should be gradual, with frequent monitoring.

Bottom Line

Although stimulant-induced psychosis is a rare occurrence, determine if your pediatric patient with attention-deficit/hyperactivity disorder (ADHD) has a family history of mood or psychotic disorders before initiating stimulants. Carefully monitor all patients for any adverse effects of stimulant medications prescribed for ADHD. If psychotic symptoms occur at therapeutic doses, reduce the dose or discontinue the medication. Once the psychotic or manic symptoms resolve, it may be appropriate to re-challenge with a stimulant.

Related Resource

• Man KK, Coghill D, Chan EW, et al. Methylphenidate and the risk of psychotic disorders and hallucinations in children and adolescents in a large health system. Transl Psychiatry. 2016;6(11):e956. doi: 10.1038/tp.2016.216.

Drug Brand Names

Atomoxetine • Strattera
Dexmethylphenidate • Focalin
Dextroamphetamine/amphetamine • Adderall
Methylphenidate • Metadate, Ritalin
Methylphenidate ER • Concerta

CASE Disruptive and inattentive

R, age 9, is brought by his mother to our child/adolescent psychiatry clinic, where he has been receiving treatment for attention-deficit/hyperactivity disorder (ADHD), because he is experiencing visual hallucinations and exhibiting aggressive behavior. R had initially been prescribed (and had been taking) short-acting methylphenidate, 5 mg every morning for weeks. During this time, he responded well to the medication; he had reduced hyperactivity, talked less in class, and was able to give increased attention to his academic work. After 2 weeks, because R did not want to take short-acting methylphenidate in school, we switched him to osmotic-controlled release oral delivery system (OROS) methylphenidate, 18 mg every morning.

Two days after starting the OROS methyl­phenidate formulation, R develops visual hallucinations and aggressive behavior. His visual hallucinations—which occur both at home and at school—involve seeing snakes circling him. When hallucinating, he hits and pushes family members and throws objects at them. He refuses to go to school because he fears the snakes. The hallucinations continue throughout the day and persist for the next 3 to 4 days.

R does not have any comorbid medical or psychiatric illnesses; however, his father has a history of schizophrenia, polysubstance abuse, and multiple prior psychiatric hospitalizations due to medication noncompliance.

R undergoes laboratory workup, which includes a complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone level, and urine drug screening. All results are within normal limits.

[polldaddy:10468215]

The authors’ observations

We ruled out delirium by ordering a basic laboratory workup. We considered the possibility of a new mood or psychotic disorder, but began to suspect the OROS methylphenidate might be causing R’s symptoms.

Attention-deficit/hyperactivity disorder is an increasingly prevalent diagnosis in the United States, affecting up to 6.4 million children age 4 to 17. While symptoms of ADHD often first appear in preschool-age children, the average age at which a child receives a diagnosis of ADHD is 7.

Stimulants are a clinically effective treatment for ADHD. In general, their use is safe and well tolerated, especially in pediatric patients. Some common adverse effects of stimulant medications include reduced appetite, headache, and insomnia.¹ Psychotic symptoms such as paranoid delusions, visual hallucinations, auditory hallucinations, and tactile hallucinations are rare. In some cases, these psychotic symptoms can be accompanied by increased aggression.^2-4

Continue to: Methylphenidate is one of the most...

Methylphenidate is one of the most commonly prescribed stimulants for treating ADHD. Methylphenidate has 2 known mechanisms of action: 1) inhibition of catecholamine reuptake at the presynaptic dopamine reuptake inhibitor, and 2) binding to and blocking intracellular dopamine transporters, inhibiting both dopamine and norepinephrine reuptake.^5,6 Because increased levels of synaptic dopamine are implicated in the generation of psychotic symptoms, the pharmacologic mechanism of methylphenidate also implies a potential to induce psychotic symptoms.⁷

How common is this problem?

On the population level, there is no detectable difference in the event rate (incidence) of psychosis in children treated with stimulants or children not taking stimulants.⁸ However, there are reports that individual patients can experience psychosis due to treatment with stimulants as an unusual adverse medication reaction. In 1971, Lucas and Weiss⁹ were among the first to describe 3 cases of methylphenidate-induced psychosis. Since then, many articles in the scientific literature have reported cases of psychosis related to stimulant medications.

A brief review of the literature between 2002 and 2010 revealed 14 cases of stimulant-related psychosis, in patients ranging from age 7 to 45. Six of the patients were children, age 7 to 12; 1 patient was an adolescent, age 15; 4 were young adults, age 18 to 25; and 3 were older adults. Of all 14 individuals, 7 reported visual hallucinations, 4 had tactile hallucinations, 4 had auditory hallucinations, and 3 displayed paranoid delusions.¹⁰ With the aim of exploring possible etiologic factors associated with psychotic symptoms, such as type of drug and dosage, it was found that 9 patients received methylphenidate, with total daily doses ranging from 7.5 to 74 mg (3 patients received short-acting methylphenidate; 1 patient received methylphenidate extended release (ER); 1 patient received both; 4 patients received dextroamphetamine, with doses of 30 to 50 mg/d; and 1 patient received amphetamine, 10 mg/d). In terms of family history, 1 patient had a positive family history of schizophrenia; 1 patient had a family history of bipolar disorder; and 6 patients were negative for family history of any psychotic disorder.¹⁰

In 2006, due to growing concerns about adverse psychiatric effects of ADHD medications, the FDA Center for Drug Evaluation and Research Office of Surveillance and Epidemiology requested the electronic clinical trial databases of manufacturers of drugs approved for the treatment of ADHD, or those with active clinical development programs for the same indication.¹¹ In that study, Mosholder et al¹¹ analyzed data from 49 randomized, controlled clinical trials that were in pediatric development programs and found that there were psychotic or manic adverse events in 11 individuals in the pooled active drug group. These were observed with methylphenidate, dexmethylphenidate, and atomoxetine. There were no events in the placebo group, which reinforced the causality between the ADHD medication and these symptoms, as participants with untreated ADHD did not develop them.¹¹

It is important to note that ADHD medications taken in excessive doses are much more likely to provoke psychotic adverse effects than when taken at therapeutic doses. However, as seen in our clinical case, patients such as R could develop acute psychosis even with a lower dosage of stimulant medications. An article by Ross² suggested rates of .25% for this psychiatric adverse effect (1 in 400 children treated with therapeutic doses of stimulants will develop psychosis), which is consistent with the data from the Mosholder et al¹¹ study.

Continue to: TREATMENT Discontinuation and re-challenge

After 3 days, we discontinue OROS methylphenidate. Five days after discontinuation, R’s visual hallucinations and aggressive behaviors completely resolve. After not receiving stimulants for 2 weeks, R is restarted on short-acting methylphenidate, 5 mg/d, because he had a relatively good clinical response to short-acting methylphenidate previously. After 14 days, the short-acting methylphenidate dosage is increased to 5 mg twice daily without the re-emergence of psychosis or aggressive behaviors.

The authors’ observations

Although stimulant-induced psychosis can be a disturbing adverse effect, severe ADHD greatly affects a person’s functioning at school and at home and can lead to several comorbidities, including depression, anxiety, and substance abuse. For these reasons, most patients with ADHD who experience psychotic symptoms are re-challenged with stimulants.¹⁰ Out of the 14 cases discussed above, 4 patients were restarted on the same stimulant or a different ADHD medication; 2 of them had the same psychotic symptoms days after the reintroduction of the drug and the other 2 had no recurrence.^10,12,13

Stimulant-induced hallucinations

The emergence of hallucinations with methylphenidate or amphetamines has been attributed to a chronic increase of dopamine levels in the synaptic cleft, while the pathophysiological mechanisms are not clearly known. In some cases, hallucinations emerged after taking the first low dose, which has been thought to be an effect of idiosyncratic mechanism. Stimulants cause an increase of the releasing of catecholamines. Porfirio et al¹⁴ argue that high-dose stimulants can deteriorate the response to visual stimuli, causing a different perception of visual stimuli in susceptible children, based on the information that norepinephrine is released in the lateral geniculate nucleus, and it increases the transmission of visual information.

An idiosyncratic drug reaction

Despite the existence of many theories on the pathophysiology of stimulant-induced psychosis (Box^15-18), its actual mechanism remains unknown. In R’s case, given the speed with which his symptoms developed, the proposed mechanisms of action may not explain his psychotic symptoms. We must consider an idiosyncratic drug reaction as an explanation. This suggestion is supported by the fact that re-challenging with a stimulant did not re-induce psychosis in 2 out of the 4 cases described in the literature,^10,12,13 as well as in R’s case.

Box

Although the mechanisms by which psychotic symptoms associated with stimulants occur remain unknown, possibilities include^10,19:

• genetic predisposition
• changes induced by stimulants at the level of neurotransmitters, synapses, and brain circuits
• an idiosyncratic drug reaction.

Continue to: What to consider before prescribing stimulants

While stimulants are clearly beneficial for the vast majority of children with ADHD, there may be a small subgroup of patients for whom stimulants carry increased risk. For example, it is possible that patients with a family history of mood and psychotic disorders may be more vulnerable to stimulant-induced psychotic symptoms that are reversible on discontinuation.²⁰ In our case, R had a first-degree relative (his father) with treatment-refractory schizophrenia.

Attentional dysfunction is a common premorbid presentation for children who later develop schizophrenia or bipolar disorder. Retrospective data from patients with schizophrenia or bipolar disorder document high rates of childhood stimulant use—generally higher even than other groups with attentional dysfunction²¹ and histories of stimulant-associated adverse behavioral effects.²² In these patients, a history of stimulant use is also associated with an earlier age at onset²³ and a more severe course of illness during hospitalization.²⁴ Stimulant exposure in vulnerable individuals may hasten the onset or worsen the course of bipolar or psychotic illnesses.^21,25,26

OUTCOME Well-controlled symptoms

R continues to receive short-acting methylphenidate, 5 mg twice a day. His ADHD symptoms remain well-controlled, and he is able to do well academically.

The authors’ observations

Although stimulant-induced psychosis is a rare and unpredictable occurrence, carefully monitoring all patients for any adverse effects of ADHD medication is recommended. When present, psychotic symptoms may quickly remit upon discontinuation of the medication. The question of subsequently reintroducing stimulant medication for a patient with severe ADHD is complicated. One needs to measure the possible risk of a reoccurrence of the psychotic symptoms against the consequences of untreated ADHD. These consequences include increased risk for academic and occupational failure, depression, anxiety, and substance abuse. Psychosocial interventions for ADHD should be implemented, but for optimal results, they often need to be combined with medication. However, if a stimulant medication is to be reintroduced, this should be done with extreme care. Starting dosages need to be low, and increases should be gradual, with frequent monitoring.

Bottom Line

Although stimulant-induced psychosis is a rare occurrence, determine if your pediatric patient with attention-deficit/hyperactivity disorder (ADHD) has a family history of mood or psychotic disorders before initiating stimulants. Carefully monitor all patients for any adverse effects of stimulant medications prescribed for ADHD. If psychotic symptoms occur at therapeutic doses, reduce the dose or discontinue the medication. Once the psychotic or manic symptoms resolve, it may be appropriate to re-challenge with a stimulant.

Related Resource

• Man KK, Coghill D, Chan EW, et al. Methylphenidate and the risk of psychotic disorders and hallucinations in children and adolescents in a large health system. Transl Psychiatry. 2016;6(11):e956. doi: 10.1038/tp.2016.216.

Drug Brand Names

Atomoxetine • Strattera
Dexmethylphenidate • Focalin
Dextroamphetamine/amphetamine • Adderall
Methylphenidate • Metadate, Ritalin
Methylphenidate ER • Concerta

CASE Disruptive and inattentive

R, age 9, is brought by his mother to our child/adolescent psychiatry clinic, where he has been receiving treatment for attention-deficit/hyperactivity disorder (ADHD), because he is experiencing visual hallucinations and exhibiting aggressive behavior. R had initially been prescribed (and had been taking) short-acting methylphenidate, 5 mg every morning for weeks. During this time, he responded well to the medication; he had reduced hyperactivity, talked less in class, and was able to give increased attention to his academic work. After 2 weeks, because R did not want to take short-acting methylphenidate in school, we switched him to osmotic-controlled release oral delivery system (OROS) methylphenidate, 18 mg every morning.

Two days after starting the OROS methyl­phenidate formulation, R develops visual hallucinations and aggressive behavior. His visual hallucinations—which occur both at home and at school—involve seeing snakes circling him. When hallucinating, he hits and pushes family members and throws objects at them. He refuses to go to school because he fears the snakes. The hallucinations continue throughout the day and persist for the next 3 to 4 days.

R does not have any comorbid medical or psychiatric illnesses; however, his father has a history of schizophrenia, polysubstance abuse, and multiple prior psychiatric hospitalizations due to medication noncompliance.

R undergoes laboratory workup, which includes a complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone level, and urine drug screening. All results are within normal limits.

[polldaddy:10468215]

The authors’ observations

We ruled out delirium by ordering a basic laboratory workup. We considered the possibility of a new mood or psychotic disorder, but began to suspect the OROS methylphenidate might be causing R’s symptoms.

Attention-deficit/hyperactivity disorder is an increasingly prevalent diagnosis in the United States, affecting up to 6.4 million children age 4 to 17. While symptoms of ADHD often first appear in preschool-age children, the average age at which a child receives a diagnosis of ADHD is 7.

Stimulants are a clinically effective treatment for ADHD. In general, their use is safe and well tolerated, especially in pediatric patients. Some common adverse effects of stimulant medications include reduced appetite, headache, and insomnia.¹ Psychotic symptoms such as paranoid delusions, visual hallucinations, auditory hallucinations, and tactile hallucinations are rare. In some cases, these psychotic symptoms can be accompanied by increased aggression.^2-4

Continue to: Methylphenidate is one of the most...

Methylphenidate is one of the most commonly prescribed stimulants for treating ADHD. Methylphenidate has 2 known mechanisms of action: 1) inhibition of catecholamine reuptake at the presynaptic dopamine reuptake inhibitor, and 2) binding to and blocking intracellular dopamine transporters, inhibiting both dopamine and norepinephrine reuptake.^5,6 Because increased levels of synaptic dopamine are implicated in the generation of psychotic symptoms, the pharmacologic mechanism of methylphenidate also implies a potential to induce psychotic symptoms.⁷

How common is this problem?

On the population level, there is no detectable difference in the event rate (incidence) of psychosis in children treated with stimulants or children not taking stimulants.⁸ However, there are reports that individual patients can experience psychosis due to treatment with stimulants as an unusual adverse medication reaction. In 1971, Lucas and Weiss⁹ were among the first to describe 3 cases of methylphenidate-induced psychosis. Since then, many articles in the scientific literature have reported cases of psychosis related to stimulant medications.

A brief review of the literature between 2002 and 2010 revealed 14 cases of stimulant-related psychosis, in patients ranging from age 7 to 45. Six of the patients were children, age 7 to 12; 1 patient was an adolescent, age 15; 4 were young adults, age 18 to 25; and 3 were older adults. Of all 14 individuals, 7 reported visual hallucinations, 4 had tactile hallucinations, 4 had auditory hallucinations, and 3 displayed paranoid delusions.¹⁰ With the aim of exploring possible etiologic factors associated with psychotic symptoms, such as type of drug and dosage, it was found that 9 patients received methylphenidate, with total daily doses ranging from 7.5 to 74 mg (3 patients received short-acting methylphenidate; 1 patient received methylphenidate extended release (ER); 1 patient received both; 4 patients received dextroamphetamine, with doses of 30 to 50 mg/d; and 1 patient received amphetamine, 10 mg/d). In terms of family history, 1 patient had a positive family history of schizophrenia; 1 patient had a family history of bipolar disorder; and 6 patients were negative for family history of any psychotic disorder.¹⁰

In 2006, due to growing concerns about adverse psychiatric effects of ADHD medications, the FDA Center for Drug Evaluation and Research Office of Surveillance and Epidemiology requested the electronic clinical trial databases of manufacturers of drugs approved for the treatment of ADHD, or those with active clinical development programs for the same indication.¹¹ In that study, Mosholder et al¹¹ analyzed data from 49 randomized, controlled clinical trials that were in pediatric development programs and found that there were psychotic or manic adverse events in 11 individuals in the pooled active drug group. These were observed with methylphenidate, dexmethylphenidate, and atomoxetine. There were no events in the placebo group, which reinforced the causality between the ADHD medication and these symptoms, as participants with untreated ADHD did not develop them.¹¹

It is important to note that ADHD medications taken in excessive doses are much more likely to provoke psychotic adverse effects than when taken at therapeutic doses. However, as seen in our clinical case, patients such as R could develop acute psychosis even with a lower dosage of stimulant medications. An article by Ross² suggested rates of .25% for this psychiatric adverse effect (1 in 400 children treated with therapeutic doses of stimulants will develop psychosis), which is consistent with the data from the Mosholder et al¹¹ study.

Continue to: TREATMENT Discontinuation and re-challenge

After 3 days, we discontinue OROS methylphenidate. Five days after discontinuation, R’s visual hallucinations and aggressive behaviors completely resolve. After not receiving stimulants for 2 weeks, R is restarted on short-acting methylphenidate, 5 mg/d, because he had a relatively good clinical response to short-acting methylphenidate previously. After 14 days, the short-acting methylphenidate dosage is increased to 5 mg twice daily without the re-emergence of psychosis or aggressive behaviors.

The authors’ observations

Although stimulant-induced psychosis can be a disturbing adverse effect, severe ADHD greatly affects a person’s functioning at school and at home and can lead to several comorbidities, including depression, anxiety, and substance abuse. For these reasons, most patients with ADHD who experience psychotic symptoms are re-challenged with stimulants.¹⁰ Out of the 14 cases discussed above, 4 patients were restarted on the same stimulant or a different ADHD medication; 2 of them had the same psychotic symptoms days after the reintroduction of the drug and the other 2 had no recurrence.^10,12,13

Stimulant-induced hallucinations

The emergence of hallucinations with methylphenidate or amphetamines has been attributed to a chronic increase of dopamine levels in the synaptic cleft, while the pathophysiological mechanisms are not clearly known. In some cases, hallucinations emerged after taking the first low dose, which has been thought to be an effect of idiosyncratic mechanism. Stimulants cause an increase of the releasing of catecholamines. Porfirio et al¹⁴ argue that high-dose stimulants can deteriorate the response to visual stimuli, causing a different perception of visual stimuli in susceptible children, based on the information that norepinephrine is released in the lateral geniculate nucleus, and it increases the transmission of visual information.

An idiosyncratic drug reaction

Despite the existence of many theories on the pathophysiology of stimulant-induced psychosis (Box^15-18), its actual mechanism remains unknown. In R’s case, given the speed with which his symptoms developed, the proposed mechanisms of action may not explain his psychotic symptoms. We must consider an idiosyncratic drug reaction as an explanation. This suggestion is supported by the fact that re-challenging with a stimulant did not re-induce psychosis in 2 out of the 4 cases described in the literature,^10,12,13 as well as in R’s case.

Box

Although the mechanisms by which psychotic symptoms associated with stimulants occur remain unknown, possibilities include^10,19:

• genetic predisposition
• changes induced by stimulants at the level of neurotransmitters, synapses, and brain circuits
• an idiosyncratic drug reaction.

Continue to: What to consider before prescribing stimulants

While stimulants are clearly beneficial for the vast majority of children with ADHD, there may be a small subgroup of patients for whom stimulants carry increased risk. For example, it is possible that patients with a family history of mood and psychotic disorders may be more vulnerable to stimulant-induced psychotic symptoms that are reversible on discontinuation.²⁰ In our case, R had a first-degree relative (his father) with treatment-refractory schizophrenia.

Attentional dysfunction is a common premorbid presentation for children who later develop schizophrenia or bipolar disorder. Retrospective data from patients with schizophrenia or bipolar disorder document high rates of childhood stimulant use—generally higher even than other groups with attentional dysfunction²¹ and histories of stimulant-associated adverse behavioral effects.²² In these patients, a history of stimulant use is also associated with an earlier age at onset²³ and a more severe course of illness during hospitalization.²⁴ Stimulant exposure in vulnerable individuals may hasten the onset or worsen the course of bipolar or psychotic illnesses.^21,25,26

OUTCOME Well-controlled symptoms

R continues to receive short-acting methylphenidate, 5 mg twice a day. His ADHD symptoms remain well-controlled, and he is able to do well academically.

The authors’ observations

Although stimulant-induced psychosis is a rare and unpredictable occurrence, carefully monitoring all patients for any adverse effects of ADHD medication is recommended. When present, psychotic symptoms may quickly remit upon discontinuation of the medication. The question of subsequently reintroducing stimulant medication for a patient with severe ADHD is complicated. One needs to measure the possible risk of a reoccurrence of the psychotic symptoms against the consequences of untreated ADHD. These consequences include increased risk for academic and occupational failure, depression, anxiety, and substance abuse. Psychosocial interventions for ADHD should be implemented, but for optimal results, they often need to be combined with medication. However, if a stimulant medication is to be reintroduced, this should be done with extreme care. Starting dosages need to be low, and increases should be gradual, with frequent monitoring.

Bottom Line

Although stimulant-induced psychosis is a rare occurrence, determine if your pediatric patient with attention-deficit/hyperactivity disorder (ADHD) has a family history of mood or psychotic disorders before initiating stimulants. Carefully monitor all patients for any adverse effects of stimulant medications prescribed for ADHD. If psychotic symptoms occur at therapeutic doses, reduce the dose or discontinue the medication. Once the psychotic or manic symptoms resolve, it may be appropriate to re-challenge with a stimulant.

Related Resource

• Man KK, Coghill D, Chan EW, et al. Methylphenidate and the risk of psychotic disorders and hallucinations in children and adolescents in a large health system. Transl Psychiatry. 2016;6(11):e956. doi: 10.1038/tp.2016.216.

Drug Brand Names

Atomoxetine • Strattera
Dexmethylphenidate • Focalin
Dextroamphetamine/amphetamine • Adderall
Methylphenidate • Metadate, Ritalin
Methylphenidate ER • Concerta

Women with ADHD, autism spectrum disorder (ASD), or both report higher rates of chronic pain, which should be accounted for in the treatment received, new research shows.

In some cases, treating the ADHD might lower the pain, reported Karin Asztély of the Sahlgrenska Academy Institute of Neuroscience, Göteborg, Sweden, and associates. The study was published in the Journal of Pain Research.

The research included 77 Swedish women with ADHD, ASD, or both from a larger prospective longitudinal study. From 2015 to 2018, when the women were aged 19-37 years, they were contacted by mail and phone, and interviewed about symptoms of pain. This included chronic widespread or regional symptoms of pain; widespread pain was pain that lasted more than 3 months and was described both above and below the waist, on both sides of the body, and in the axial skeleton. Any pain that lasted more than 3 months but did not meet those other requirements was listed as chronic regional pain.

Chronic pain of any kind was reported by 59 participants (76.6%). Chronic widespread pain was reported by 25 participants (32.5%), and chronic regional pain was reported by 34 (44.2%), both of which were higher than those seen in a cross-sectional survey, which showed prevalences of 11.9% and 23.9% of Swedish participants, respectively (J Rheumatol. 2001 Jun;28[6]:1369-77).

Among the limitations of the latest study is the small sample size and the absence of healthy controls; however, the researchers thought this was compensated for by the comparisons with previous research.

“Our findings highlight the importance of the health care professionals to address pain problems in this patient group and possible unrecognized ASD and/or ADHD in women with chronic pain,” they concluded.

The investigators reported no conflicts of interest.

cpalmer@mdedge.com

SOURCE: Asztély et al. J Pain Res. 2019 Oct 18;12:2925-32.

Women with ADHD, autism spectrum disorder (ASD), or both report higher rates of chronic pain, which should be accounted for in the treatment received, new research shows.

In some cases, treating the ADHD might lower the pain, reported Karin Asztély of the Sahlgrenska Academy Institute of Neuroscience, Göteborg, Sweden, and associates. The study was published in the Journal of Pain Research.

The research included 77 Swedish women with ADHD, ASD, or both from a larger prospective longitudinal study. From 2015 to 2018, when the women were aged 19-37 years, they were contacted by mail and phone, and interviewed about symptoms of pain. This included chronic widespread or regional symptoms of pain; widespread pain was pain that lasted more than 3 months and was described both above and below the waist, on both sides of the body, and in the axial skeleton. Any pain that lasted more than 3 months but did not meet those other requirements was listed as chronic regional pain.

Chronic pain of any kind was reported by 59 participants (76.6%). Chronic widespread pain was reported by 25 participants (32.5%), and chronic regional pain was reported by 34 (44.2%), both of which were higher than those seen in a cross-sectional survey, which showed prevalences of 11.9% and 23.9% of Swedish participants, respectively (J Rheumatol. 2001 Jun;28[6]:1369-77).

Among the limitations of the latest study is the small sample size and the absence of healthy controls; however, the researchers thought this was compensated for by the comparisons with previous research.

“Our findings highlight the importance of the health care professionals to address pain problems in this patient group and possible unrecognized ASD and/or ADHD in women with chronic pain,” they concluded.

The investigators reported no conflicts of interest.

cpalmer@mdedge.com

SOURCE: Asztély et al. J Pain Res. 2019 Oct 18;12:2925-32.

Women with ADHD, autism spectrum disorder (ASD), or both report higher rates of chronic pain, which should be accounted for in the treatment received, new research shows.

In some cases, treating the ADHD might lower the pain, reported Karin Asztély of the Sahlgrenska Academy Institute of Neuroscience, Göteborg, Sweden, and associates. The study was published in the Journal of Pain Research.

The research included 77 Swedish women with ADHD, ASD, or both from a larger prospective longitudinal study. From 2015 to 2018, when the women were aged 19-37 years, they were contacted by mail and phone, and interviewed about symptoms of pain. This included chronic widespread or regional symptoms of pain; widespread pain was pain that lasted more than 3 months and was described both above and below the waist, on both sides of the body, and in the axial skeleton. Any pain that lasted more than 3 months but did not meet those other requirements was listed as chronic regional pain.

Chronic pain of any kind was reported by 59 participants (76.6%). Chronic widespread pain was reported by 25 participants (32.5%), and chronic regional pain was reported by 34 (44.2%), both of which were higher than those seen in a cross-sectional survey, which showed prevalences of 11.9% and 23.9% of Swedish participants, respectively (J Rheumatol. 2001 Jun;28[6]:1369-77).

Among the limitations of the latest study is the small sample size and the absence of healthy controls; however, the researchers thought this was compensated for by the comparisons with previous research.

“Our findings highlight the importance of the health care professionals to address pain problems in this patient group and possible unrecognized ASD and/or ADHD in women with chronic pain,” they concluded.

The investigators reported no conflicts of interest.

cpalmer@mdedge.com

SOURCE: Asztély et al. J Pain Res. 2019 Oct 18;12:2925-32.

A qualitative investigation based on interviews with successful adults with ADHD identified six core themes that are positive aspects of ADHD.

Under a phenomenology framework, purposive sampling was used to enroll six successful male participants with ADHD diagnoses. The participants were interviewed in an open-ended way and were assessed with theme content analysis, reported Jane Ann Sedgwick, a PhD candidate within the MRC Social, Genetic & Developmental Psychiatry Center at King’s College London, and coauthors. The six core themes identified were cognitive dynamism, courage, energy, humanity, resilience, and transcendence. They then compared those themes with attributes cataloged in a handbook by Christopher Petersen and Marten E.P. Seligman (Character Strengths and Virtues: A Handbook and Classification. Washington: American Psychological Association and Oxford University Press, 2004). The study was published in ADHD: Attention Deficit and Hyperactivity Disorders.

Because energy and cognitive dynamism as discussed in the present research were not cataloged in that handbook, they were unique to ADHD, according to Ms. Sedgwick and coauthors. The theme of energy described “participants’ reports about internal experiences and capacity for action,” with subthemes of spirit, which embraces higher aspects of self, sense of purpose, and meaning in life; psychological energy, including drive and volition; and physical energy, which can manifest as interest in and enjoyment of activities such as sports. Meanwhile, cognitive dynamism describes the “ceaseless mental activity that was reported by all participants,” including subthemes of divergent thinking, hyperfocus, creativity, and curiosity.

Limitations of the study included the shortcomings within the phenomenological framework, which requires participants who are capable of being articulate, expressive, and reflective. Another is the small sample size and absence of female participants.

“Too often people with lived experience hear about ADHD in relation to deficits, functional impairments, and associations with substance misuse, criminality, or other disadvantages on almost every level of life (school, work, relationships),” Ms. Sedgwick and her coauthors wrote. “This study affirms the positive human qualities, assets, and attributes in ADHD that can promote high functioning and flourishing.”

cpalmer@mdedge.com

A qualitative investigation based on interviews with successful adults with ADHD identified six core themes that are positive aspects of ADHD.

Under a phenomenology framework, purposive sampling was used to enroll six successful male participants with ADHD diagnoses. The participants were interviewed in an open-ended way and were assessed with theme content analysis, reported Jane Ann Sedgwick, a PhD candidate within the MRC Social, Genetic & Developmental Psychiatry Center at King’s College London, and coauthors. The six core themes identified were cognitive dynamism, courage, energy, humanity, resilience, and transcendence. They then compared those themes with attributes cataloged in a handbook by Christopher Petersen and Marten E.P. Seligman (Character Strengths and Virtues: A Handbook and Classification. Washington: American Psychological Association and Oxford University Press, 2004). The study was published in ADHD: Attention Deficit and Hyperactivity Disorders.

Because energy and cognitive dynamism as discussed in the present research were not cataloged in that handbook, they were unique to ADHD, according to Ms. Sedgwick and coauthors. The theme of energy described “participants’ reports about internal experiences and capacity for action,” with subthemes of spirit, which embraces higher aspects of self, sense of purpose, and meaning in life; psychological energy, including drive and volition; and physical energy, which can manifest as interest in and enjoyment of activities such as sports. Meanwhile, cognitive dynamism describes the “ceaseless mental activity that was reported by all participants,” including subthemes of divergent thinking, hyperfocus, creativity, and curiosity.

Limitations of the study included the shortcomings within the phenomenological framework, which requires participants who are capable of being articulate, expressive, and reflective. Another is the small sample size and absence of female participants.

“Too often people with lived experience hear about ADHD in relation to deficits, functional impairments, and associations with substance misuse, criminality, or other disadvantages on almost every level of life (school, work, relationships),” Ms. Sedgwick and her coauthors wrote. “This study affirms the positive human qualities, assets, and attributes in ADHD that can promote high functioning and flourishing.”

cpalmer@mdedge.com

A qualitative investigation based on interviews with successful adults with ADHD identified six core themes that are positive aspects of ADHD.

Under a phenomenology framework, purposive sampling was used to enroll six successful male participants with ADHD diagnoses. The participants were interviewed in an open-ended way and were assessed with theme content analysis, reported Jane Ann Sedgwick, a PhD candidate within the MRC Social, Genetic & Developmental Psychiatry Center at King’s College London, and coauthors. The six core themes identified were cognitive dynamism, courage, energy, humanity, resilience, and transcendence. They then compared those themes with attributes cataloged in a handbook by Christopher Petersen and Marten E.P. Seligman (Character Strengths and Virtues: A Handbook and Classification. Washington: American Psychological Association and Oxford University Press, 2004). The study was published in ADHD: Attention Deficit and Hyperactivity Disorders.

Because energy and cognitive dynamism as discussed in the present research were not cataloged in that handbook, they were unique to ADHD, according to Ms. Sedgwick and coauthors. The theme of energy described “participants’ reports about internal experiences and capacity for action,” with subthemes of spirit, which embraces higher aspects of self, sense of purpose, and meaning in life; psychological energy, including drive and volition; and physical energy, which can manifest as interest in and enjoyment of activities such as sports. Meanwhile, cognitive dynamism describes the “ceaseless mental activity that was reported by all participants,” including subthemes of divergent thinking, hyperfocus, creativity, and curiosity.

Limitations of the study included the shortcomings within the phenomenological framework, which requires participants who are capable of being articulate, expressive, and reflective. Another is the small sample size and absence of female participants.

“Too often people with lived experience hear about ADHD in relation to deficits, functional impairments, and associations with substance misuse, criminality, or other disadvantages on almost every level of life (school, work, relationships),” Ms. Sedgwick and her coauthors wrote. “This study affirms the positive human qualities, assets, and attributes in ADHD that can promote high functioning and flourishing.”

cpalmer@mdedge.com

SAN DIEGO – Research suggests that as many as 23% of patients with substance use disorder (SUD) also have ADHD, adding an extra layer of complexity to a difficult-to-treat condition. What to do?

“Treating the ADHD can be useful in reducing the severity of symptoms without worsening the substance use disorder. It shouldn’t be avoided,” said psychiatrist Larissa J. Mooney, MD, of the University of California, Los Angeles, and the Veterans Affairs Greater Los Angeles Healthcare System, in a presentation at the annual Psych Congress.

When ADHD is on board, “it’s a more complicated and challenging clinical course,” Dr. Mooney said. The duo of disorders is linked to higher rates of polysubstance abuse and other psychiatric conditions, such as anxiety, bipolar disorder, posttraumatic stress, and antisocial/borderline conditions (Eur Addict Res. 2018;24[1]:43-51).

“These individuals typically have more difficulty with [drug] abstinence, more health consequences, and reduced quality of life, and social and professional consequences,” she said. “Some studies have suggested that they may not respond to lower doses of medication for attention-deficit/hyperactivity disorder and may require doses in the higher range.”

Research has hinted that several drugs that might prove helpful in these patients by improving both conditions, Dr. Mooney said. These include up to 180 mg/day of methylphenidate (Ritalin), 60- and 80-mg doses of mixed amphetamine salts/extended release, atomoxetine (Strattera), and bupropion.

In regard to bupropion, she said, “I find it to be a good choice in my substance use disorder patients for their depression and concentration problems. I have a greater number of individuals at 450 milligrams per day and the XL formulation.”

Early research has suggested that guanfacine XR (Intuniv), which is used to treat children with ADHD, also might be helpful in adults, including those with SUD. “We need more research to show if this is helpful,” she said. “It’s a reasonable choice in terms of weighing pros and cons, because it’s not [a controlled substance].”

Still, some of those medications are stimulants, Dr. Mooney said, and their use in patients with SUD is controversial. There are concerns about misuse and diversion.

“We want to have some flexibility,” she said, but it’s important to think about risks and priorities. In certain cases, ADHD may be a secondary concern.

“Some patients have a severe substance use disorder that keeps landing them in the emergency room or causing them to be hospitalized,” she said. “I’m more worried about that than the impairment function from ADHD.”

If you do consider stimulants, she said, longer-acting formulations can be less risky because there’s less potential for diversion. “Also, think about their treatment plan: Is their functioning improving? Are they or showing up for appointments? These are factors that will say: ‘Oh, I’m on the right path with this medication.’ ”

Behavioral treatment also can be helpful in these patients, she said, although “some may not be willing or motivated to put in the time that it takes to do the behavioral work.”

Dr. Mooney disclosed an advisory board relationship with Alkermes and grant/research support from the National Institute on Drug Abuse.

SAN DIEGO – Research suggests that as many as 23% of patients with substance use disorder (SUD) also have ADHD, adding an extra layer of complexity to a difficult-to-treat condition. What to do?

“Treating the ADHD can be useful in reducing the severity of symptoms without worsening the substance use disorder. It shouldn’t be avoided,” said psychiatrist Larissa J. Mooney, MD, of the University of California, Los Angeles, and the Veterans Affairs Greater Los Angeles Healthcare System, in a presentation at the annual Psych Congress.

When ADHD is on board, “it’s a more complicated and challenging clinical course,” Dr. Mooney said. The duo of disorders is linked to higher rates of polysubstance abuse and other psychiatric conditions, such as anxiety, bipolar disorder, posttraumatic stress, and antisocial/borderline conditions (Eur Addict Res. 2018;24[1]:43-51).

“These individuals typically have more difficulty with [drug] abstinence, more health consequences, and reduced quality of life, and social and professional consequences,” she said. “Some studies have suggested that they may not respond to lower doses of medication for attention-deficit/hyperactivity disorder and may require doses in the higher range.”

Research has hinted that several drugs that might prove helpful in these patients by improving both conditions, Dr. Mooney said. These include up to 180 mg/day of methylphenidate (Ritalin), 60- and 80-mg doses of mixed amphetamine salts/extended release, atomoxetine (Strattera), and bupropion.

In regard to bupropion, she said, “I find it to be a good choice in my substance use disorder patients for their depression and concentration problems. I have a greater number of individuals at 450 milligrams per day and the XL formulation.”

Early research has suggested that guanfacine XR (Intuniv), which is used to treat children with ADHD, also might be helpful in adults, including those with SUD. “We need more research to show if this is helpful,” she said. “It’s a reasonable choice in terms of weighing pros and cons, because it’s not [a controlled substance].”

Still, some of those medications are stimulants, Dr. Mooney said, and their use in patients with SUD is controversial. There are concerns about misuse and diversion.

“We want to have some flexibility,” she said, but it’s important to think about risks and priorities. In certain cases, ADHD may be a secondary concern.

“Some patients have a severe substance use disorder that keeps landing them in the emergency room or causing them to be hospitalized,” she said. “I’m more worried about that than the impairment function from ADHD.”

If you do consider stimulants, she said, longer-acting formulations can be less risky because there’s less potential for diversion. “Also, think about their treatment plan: Is their functioning improving? Are they or showing up for appointments? These are factors that will say: ‘Oh, I’m on the right path with this medication.’ ”

Behavioral treatment also can be helpful in these patients, she said, although “some may not be willing or motivated to put in the time that it takes to do the behavioral work.”

Dr. Mooney disclosed an advisory board relationship with Alkermes and grant/research support from the National Institute on Drug Abuse.

SAN DIEGO – Research suggests that as many as 23% of patients with substance use disorder (SUD) also have ADHD, adding an extra layer of complexity to a difficult-to-treat condition. What to do?

“Treating the ADHD can be useful in reducing the severity of symptoms without worsening the substance use disorder. It shouldn’t be avoided,” said psychiatrist Larissa J. Mooney, MD, of the University of California, Los Angeles, and the Veterans Affairs Greater Los Angeles Healthcare System, in a presentation at the annual Psych Congress.

When ADHD is on board, “it’s a more complicated and challenging clinical course,” Dr. Mooney said. The duo of disorders is linked to higher rates of polysubstance abuse and other psychiatric conditions, such as anxiety, bipolar disorder, posttraumatic stress, and antisocial/borderline conditions (Eur Addict Res. 2018;24[1]:43-51).

“These individuals typically have more difficulty with [drug] abstinence, more health consequences, and reduced quality of life, and social and professional consequences,” she said. “Some studies have suggested that they may not respond to lower doses of medication for attention-deficit/hyperactivity disorder and may require doses in the higher range.”

Research has hinted that several drugs that might prove helpful in these patients by improving both conditions, Dr. Mooney said. These include up to 180 mg/day of methylphenidate (Ritalin), 60- and 80-mg doses of mixed amphetamine salts/extended release, atomoxetine (Strattera), and bupropion.

In regard to bupropion, she said, “I find it to be a good choice in my substance use disorder patients for their depression and concentration problems. I have a greater number of individuals at 450 milligrams per day and the XL formulation.”

Early research has suggested that guanfacine XR (Intuniv), which is used to treat children with ADHD, also might be helpful in adults, including those with SUD. “We need more research to show if this is helpful,” she said. “It’s a reasonable choice in terms of weighing pros and cons, because it’s not [a controlled substance].”

Still, some of those medications are stimulants, Dr. Mooney said, and their use in patients with SUD is controversial. There are concerns about misuse and diversion.

“We want to have some flexibility,” she said, but it’s important to think about risks and priorities. In certain cases, ADHD may be a secondary concern.

“Some patients have a severe substance use disorder that keeps landing them in the emergency room or causing them to be hospitalized,” she said. “I’m more worried about that than the impairment function from ADHD.”

If you do consider stimulants, she said, longer-acting formulations can be less risky because there’s less potential for diversion. “Also, think about their treatment plan: Is their functioning improving? Are they or showing up for appointments? These are factors that will say: ‘Oh, I’m on the right path with this medication.’ ”

Behavioral treatment also can be helpful in these patients, she said, although “some may not be willing or motivated to put in the time that it takes to do the behavioral work.”

Dr. Mooney disclosed an advisory board relationship with Alkermes and grant/research support from the National Institute on Drug Abuse.

A novel robot-assisted, gamelike test accurately classified ADHD type in elementary school–aged children, according to Mun-Taek Choi, PhD, and associates.

A total of 326 children in the third and fourth grades were included in the study, 35 of whom had been diagnosed with ADHD and 26 of whom were at risk. For the 10- to 12-minute test, participants followed a robot on a path across a numbered mat while stimuli were shown on a TV with both images and sound, and completed a task at each numbered square, reported Dr. Choi, of Sungkyunkwan University, Suwan, South Korea, and associates. The study was published in the Journal of Intelligent & Robotic Systems.

Inattentive and hyperactive-impulsive behavior was measured by the number of omission and commission errors. Response time and task completion time contributed to the measure of inattentive and hyperactive-impulsive behavior. Working memory deficits were measured as deviations in the prescribed route.

The tool was able to identify the children with ADHD with a high degree of accuracy, up to a maximum of 97%. This figure improved over the course of the study as the tool learned more, indicating that generalization errors were not a serious issue for the tool, the investigators noted.

“Unlike conventional questionnaire-based tests, the robot-assisted test increases the accuracy of ADHD diagnosis by directly reflecting the quality of children’s behavior during the activity game with the robot involved in the action. Since the test obtains behavioral patterns and levels using robotic sensing technologies, it can reliably determine the three key elements of ADHD diagnosis: hyperactivity, inattentive behavior, and working memory,” the investigators wrote. Ultimately, Dr. Choi and associates wrote, the tool could help clinicians diagnose childhood ADHD.

The study was funded by the South Korean Ministry of Trade, Industry, & Energy. No disclosures were reported.

lfranki@mdedge.com

SOURCE: Choi M-T et al. J Intell Robot Syst. 2018 Jun 19. doi: 10.1007/s10846-018-0890-9.

A novel robot-assisted, gamelike test accurately classified ADHD type in elementary school–aged children, according to Mun-Taek Choi, PhD, and associates.

A total of 326 children in the third and fourth grades were included in the study, 35 of whom had been diagnosed with ADHD and 26 of whom were at risk. For the 10- to 12-minute test, participants followed a robot on a path across a numbered mat while stimuli were shown on a TV with both images and sound, and completed a task at each numbered square, reported Dr. Choi, of Sungkyunkwan University, Suwan, South Korea, and associates. The study was published in the Journal of Intelligent & Robotic Systems.

Inattentive and hyperactive-impulsive behavior was measured by the number of omission and commission errors. Response time and task completion time contributed to the measure of inattentive and hyperactive-impulsive behavior. Working memory deficits were measured as deviations in the prescribed route.

The tool was able to identify the children with ADHD with a high degree of accuracy, up to a maximum of 97%. This figure improved over the course of the study as the tool learned more, indicating that generalization errors were not a serious issue for the tool, the investigators noted.

“Unlike conventional questionnaire-based tests, the robot-assisted test increases the accuracy of ADHD diagnosis by directly reflecting the quality of children’s behavior during the activity game with the robot involved in the action. Since the test obtains behavioral patterns and levels using robotic sensing technologies, it can reliably determine the three key elements of ADHD diagnosis: hyperactivity, inattentive behavior, and working memory,” the investigators wrote. Ultimately, Dr. Choi and associates wrote, the tool could help clinicians diagnose childhood ADHD.

The study was funded by the South Korean Ministry of Trade, Industry, & Energy. No disclosures were reported.

lfranki@mdedge.com

SOURCE: Choi M-T et al. J Intell Robot Syst. 2018 Jun 19. doi: 10.1007/s10846-018-0890-9.

A novel robot-assisted, gamelike test accurately classified ADHD type in elementary school–aged children, according to Mun-Taek Choi, PhD, and associates.

A total of 326 children in the third and fourth grades were included in the study, 35 of whom had been diagnosed with ADHD and 26 of whom were at risk. For the 10- to 12-minute test, participants followed a robot on a path across a numbered mat while stimuli were shown on a TV with both images and sound, and completed a task at each numbered square, reported Dr. Choi, of Sungkyunkwan University, Suwan, South Korea, and associates. The study was published in the Journal of Intelligent & Robotic Systems.

Inattentive and hyperactive-impulsive behavior was measured by the number of omission and commission errors. Response time and task completion time contributed to the measure of inattentive and hyperactive-impulsive behavior. Working memory deficits were measured as deviations in the prescribed route.

The tool was able to identify the children with ADHD with a high degree of accuracy, up to a maximum of 97%. This figure improved over the course of the study as the tool learned more, indicating that generalization errors were not a serious issue for the tool, the investigators noted.

“Unlike conventional questionnaire-based tests, the robot-assisted test increases the accuracy of ADHD diagnosis by directly reflecting the quality of children’s behavior during the activity game with the robot involved in the action. Since the test obtains behavioral patterns and levels using robotic sensing technologies, it can reliably determine the three key elements of ADHD diagnosis: hyperactivity, inattentive behavior, and working memory,” the investigators wrote. Ultimately, Dr. Choi and associates wrote, the tool could help clinicians diagnose childhood ADHD.

The study was funded by the South Korean Ministry of Trade, Industry, & Energy. No disclosures were reported.

lfranki@mdedge.com

SOURCE: Choi M-T et al. J Intell Robot Syst. 2018 Jun 19. doi: 10.1007/s10846-018-0890-9.