Pediatric Irritation, Bipolar Disorder Differ in Imaging

PARIS – Longitudinal data, family studies, and recent imaging findings show distinct differences – and some similarities between severely irritable children and children with bipolar disorder.

The notion that bipolar disorder in children is characterized not by manic and depressive episodes but by very severe, chronic irritability and attention-deficit/hyperactivity disorder (ADHD) has become popular in the United States in recent years but doesn’t hold up to scientific scrutiny, Dr. Ellen Leibenluft said at the annual congress of the European College of Neuropsychopharmacology.

ADHD is common, and irritability is common within ADHD. As this new way of diagnosing pediatric bipolar disorder gained currency, U.S. diagnoses increased 40%-400% in the past decade, depending on which study you look at, said Dr. Leibenluft, chief of the section on bipolar spectrum disorders in the Emotion and Development Branch, Mood and Anxiety Program of the National Institutes of Mental Health, Bethesda, Md.

In order to investigate these issues, she and other researchers defined a syndrome called severe mood dysregulation. These are children with chronic irritability (not episodic, as in classically defined bipolar disorder), with baseline anger or sadness and increased reactivity to negative emotional stimuli at least three times per week and in two or more settings (home, school, etc.) They have ADHD symptoms that overlap with "B" mania criteria. Clinically, they are the most severely impaired, irritable children with ADHD or oppositional defiant disorder.

The distinction between bipolar disorder and severe mood dysregulation has important implications for treatment. If an assumption is made that they are the same disorder, a physician might treat with medications for bipolar disorder such as antipsychotics or anticonvulsants.

However Dr. Leibenluft presented data suggesting that it may make more sense to think of children with severe mood dysregulation as having ADHD, anxiety, and depression, in which case a consideration might be made to treat with stimulants and serotonin reuptake inhibitors (SRIs), which would be contraindicated in bipolar disorder. A trial of the latter approach is underway.

"We don’t know yet if these chronically irritable children respond well to stimulants and SRIs, but at least you wouldn’t shy away from that the way you would if you thought these children had bipolar disorder," she said.

If severe mood dysregulation is a form of bipolar disorder, these children could be expected to develop mania as they grow up, but that’s not what happens, Dr. Leibenluft said. One longitudinal analysis compared 54 children with severe mood dysregulation and 1,366 without the syndrome who were assessed at ages 8-10 years and again at age 18. The children with severe mood dysregulation had more than a sevenfold higher risk for developing major depressive disorder but were not at significantly higher risk for mania or bipolar disorder (Biol. Psychiatry 2006;60:991-7).

A separate, community-based study assessed 776 children at age 14 years and followed them to age 33. Chronic irritability in adolescence did not predict mania but did predict a 33% higher risk for major depression, a 72% higher risk for generalized anxiety disorder, and an 81% higher risk for dysthymia (Am. J. Psychiatry 2009;166:1048-54).

"A number of studies in the OCD [obsessive compulsive disorder] literature would go along with this," Dr. Leibenluft added.

Bipolar disorder is known to run in families. In one study of 33 youths with bipolar disorder, more than 30% of their parents had bipolar disorder, but in the families of 30 youths with severe mood dysregulation, fewer than 5% of parents had bipolar disorder (Am J. Psychiatry 2007;164:1238-41).

In recent functional MRI (fMRI) studies, both children with severe mood dysregulation and bipolar disorder had difficulty identifying face emotions, but the brain mechanisms behind their difficulties differed between groups.

"Brain imaging is very much a research tool, but it’s something that we can look forward to in the future as an adjunct in addition to careful clinical assessment, which will always be the hallmark of differential diagnosis," Dr. Leibenluft said.

In one study, children looked at a photo of a neutral face and were asked, "How afraid are you?" and "How wide is the nose?" The 43 children with bipolar disorder and 29 with severe mood dysregulation were significantly more likely to report fear than were the 18 children with nonirritable ADHD and 37 healthy control children. On fMRI during this task, however, only the severe mood dysregulation group showed deactivation in the left amygdala (Am. J. Psychiatry 2010;167:61-9).

At least one prior fMRI study has shown decreased amygdala activation during face emotion processing in patients with major depression (with or without anxiety), compared with patients who have anxiety alone or control patients. "Children with severe mood dysregulation are looking more like depressed children than they are like children with ADHD," Dr. Leibenluft said.

In fMRI studies that will be published soon, both 26 children with bipolar disorder and 22 children with severe mood dysregulation showed deficits in "response reversal" tasks (which would make a person more prone to experience frustration), compared with 34 control children, she said.

In this task, subjects are asked to select between two objects, told that one will win them points and the other will lose them points, and occasionally, the objects will switch roles without announcement. It’s an assessment of one’s ability to adapt to changes in the environment.

"In real life, it would sort of be as if a child is on the playground and then recess is over. The children have to change what they’re doing and adapt to the environment," Dr. Leibenluft said. "You could see how if you [weren’t able to adapt], you would end up extremely frustrated."

The fMRI studies demonstrated that when the control subjects made an error, the right caudate activated, sending them an error signal to rethink what they’re doing; the caudate did not alert the children with bipolar disorder or severe mood dysregulation.

The right inferior frontal gyrus, which plays an important role in attention when adaptation is required, activated in both the control children and those with bipolar disorder when they made an error in the task, but the children with severe mood dysregulation showed much less activation in this area, she said.

Studies will continue to tease out the similarities and differences between bipolar disorder and severe mood dysregulation as distinct categories or part of a spectrum. "This is where, ultimately, far down the line, imaging may be able to complement clinical assessment in differential diagnosis," she said.

Dr. Leibenluft’s research is funded by the National Institutes of Mental Health. The European College of Neuropsychopharmacology paid her expenses to speak at the meeting.

PARIS – Longitudinal data, family studies, and recent imaging findings show distinct differences – and some similarities between severely irritable children and children with bipolar disorder.

The notion that bipolar disorder in children is characterized not by manic and depressive episodes but by very severe, chronic irritability and attention-deficit/hyperactivity disorder (ADHD) has become popular in the United States in recent years but doesn’t hold up to scientific scrutiny, Dr. Ellen Leibenluft said at the annual congress of the European College of Neuropsychopharmacology.

ADHD is common, and irritability is common within ADHD. As this new way of diagnosing pediatric bipolar disorder gained currency, U.S. diagnoses increased 40%-400% in the past decade, depending on which study you look at, said Dr. Leibenluft, chief of the section on bipolar spectrum disorders in the Emotion and Development Branch, Mood and Anxiety Program of the National Institutes of Mental Health, Bethesda, Md.

In order to investigate these issues, she and other researchers defined a syndrome called severe mood dysregulation. These are children with chronic irritability (not episodic, as in classically defined bipolar disorder), with baseline anger or sadness and increased reactivity to negative emotional stimuli at least three times per week and in two or more settings (home, school, etc.) They have ADHD symptoms that overlap with "B" mania criteria. Clinically, they are the most severely impaired, irritable children with ADHD or oppositional defiant disorder.

The distinction between bipolar disorder and severe mood dysregulation has important implications for treatment. If an assumption is made that they are the same disorder, a physician might treat with medications for bipolar disorder such as antipsychotics or anticonvulsants.

However Dr. Leibenluft presented data suggesting that it may make more sense to think of children with severe mood dysregulation as having ADHD, anxiety, and depression, in which case a consideration might be made to treat with stimulants and serotonin reuptake inhibitors (SRIs), which would be contraindicated in bipolar disorder. A trial of the latter approach is underway.

"We don’t know yet if these chronically irritable children respond well to stimulants and SRIs, but at least you wouldn’t shy away from that the way you would if you thought these children had bipolar disorder," she said.

If severe mood dysregulation is a form of bipolar disorder, these children could be expected to develop mania as they grow up, but that’s not what happens, Dr. Leibenluft said. One longitudinal analysis compared 54 children with severe mood dysregulation and 1,366 without the syndrome who were assessed at ages 8-10 years and again at age 18. The children with severe mood dysregulation had more than a sevenfold higher risk for developing major depressive disorder but were not at significantly higher risk for mania or bipolar disorder (Biol. Psychiatry 2006;60:991-7).

A separate, community-based study assessed 776 children at age 14 years and followed them to age 33. Chronic irritability in adolescence did not predict mania but did predict a 33% higher risk for major depression, a 72% higher risk for generalized anxiety disorder, and an 81% higher risk for dysthymia (Am. J. Psychiatry 2009;166:1048-54).

"A number of studies in the OCD [obsessive compulsive disorder] literature would go along with this," Dr. Leibenluft added.

Bipolar disorder is known to run in families. In one study of 33 youths with bipolar disorder, more than 30% of their parents had bipolar disorder, but in the families of 30 youths with severe mood dysregulation, fewer than 5% of parents had bipolar disorder (Am J. Psychiatry 2007;164:1238-41).

In recent functional MRI (fMRI) studies, both children with severe mood dysregulation and bipolar disorder had difficulty identifying face emotions, but the brain mechanisms behind their difficulties differed between groups.

"Brain imaging is very much a research tool, but it’s something that we can look forward to in the future as an adjunct in addition to careful clinical assessment, which will always be the hallmark of differential diagnosis," Dr. Leibenluft said.

In one study, children looked at a photo of a neutral face and were asked, "How afraid are you?" and "How wide is the nose?" The 43 children with bipolar disorder and 29 with severe mood dysregulation were significantly more likely to report fear than were the 18 children with nonirritable ADHD and 37 healthy control children. On fMRI during this task, however, only the severe mood dysregulation group showed deactivation in the left amygdala (Am. J. Psychiatry 2010;167:61-9).

At least one prior fMRI study has shown decreased amygdala activation during face emotion processing in patients with major depression (with or without anxiety), compared with patients who have anxiety alone or control patients. "Children with severe mood dysregulation are looking more like depressed children than they are like children with ADHD," Dr. Leibenluft said.

In fMRI studies that will be published soon, both 26 children with bipolar disorder and 22 children with severe mood dysregulation showed deficits in "response reversal" tasks (which would make a person more prone to experience frustration), compared with 34 control children, she said.

In this task, subjects are asked to select between two objects, told that one will win them points and the other will lose them points, and occasionally, the objects will switch roles without announcement. It’s an assessment of one’s ability to adapt to changes in the environment.

"In real life, it would sort of be as if a child is on the playground and then recess is over. The children have to change what they’re doing and adapt to the environment," Dr. Leibenluft said. "You could see how if you [weren’t able to adapt], you would end up extremely frustrated."

The fMRI studies demonstrated that when the control subjects made an error, the right caudate activated, sending them an error signal to rethink what they’re doing; the caudate did not alert the children with bipolar disorder or severe mood dysregulation.

The right inferior frontal gyrus, which plays an important role in attention when adaptation is required, activated in both the control children and those with bipolar disorder when they made an error in the task, but the children with severe mood dysregulation showed much less activation in this area, she said.

Studies will continue to tease out the similarities and differences between bipolar disorder and severe mood dysregulation as distinct categories or part of a spectrum. "This is where, ultimately, far down the line, imaging may be able to complement clinical assessment in differential diagnosis," she said.

Dr. Leibenluft’s research is funded by the National Institutes of Mental Health. The European College of Neuropsychopharmacology paid her expenses to speak at the meeting.

PARIS – Longitudinal data, family studies, and recent imaging findings show distinct differences – and some similarities between severely irritable children and children with bipolar disorder.

The notion that bipolar disorder in children is characterized not by manic and depressive episodes but by very severe, chronic irritability and attention-deficit/hyperactivity disorder (ADHD) has become popular in the United States in recent years but doesn’t hold up to scientific scrutiny, Dr. Ellen Leibenluft said at the annual congress of the European College of Neuropsychopharmacology.

ADHD is common, and irritability is common within ADHD. As this new way of diagnosing pediatric bipolar disorder gained currency, U.S. diagnoses increased 40%-400% in the past decade, depending on which study you look at, said Dr. Leibenluft, chief of the section on bipolar spectrum disorders in the Emotion and Development Branch, Mood and Anxiety Program of the National Institutes of Mental Health, Bethesda, Md.

In order to investigate these issues, she and other researchers defined a syndrome called severe mood dysregulation. These are children with chronic irritability (not episodic, as in classically defined bipolar disorder), with baseline anger or sadness and increased reactivity to negative emotional stimuli at least three times per week and in two or more settings (home, school, etc.) They have ADHD symptoms that overlap with "B" mania criteria. Clinically, they are the most severely impaired, irritable children with ADHD or oppositional defiant disorder.

The distinction between bipolar disorder and severe mood dysregulation has important implications for treatment. If an assumption is made that they are the same disorder, a physician might treat with medications for bipolar disorder such as antipsychotics or anticonvulsants.

However Dr. Leibenluft presented data suggesting that it may make more sense to think of children with severe mood dysregulation as having ADHD, anxiety, and depression, in which case a consideration might be made to treat with stimulants and serotonin reuptake inhibitors (SRIs), which would be contraindicated in bipolar disorder. A trial of the latter approach is underway.

"We don’t know yet if these chronically irritable children respond well to stimulants and SRIs, but at least you wouldn’t shy away from that the way you would if you thought these children had bipolar disorder," she said.

If severe mood dysregulation is a form of bipolar disorder, these children could be expected to develop mania as they grow up, but that’s not what happens, Dr. Leibenluft said. One longitudinal analysis compared 54 children with severe mood dysregulation and 1,366 without the syndrome who were assessed at ages 8-10 years and again at age 18. The children with severe mood dysregulation had more than a sevenfold higher risk for developing major depressive disorder but were not at significantly higher risk for mania or bipolar disorder (Biol. Psychiatry 2006;60:991-7).

A separate, community-based study assessed 776 children at age 14 years and followed them to age 33. Chronic irritability in adolescence did not predict mania but did predict a 33% higher risk for major depression, a 72% higher risk for generalized anxiety disorder, and an 81% higher risk for dysthymia (Am. J. Psychiatry 2009;166:1048-54).

"A number of studies in the OCD [obsessive compulsive disorder] literature would go along with this," Dr. Leibenluft added.

Bipolar disorder is known to run in families. In one study of 33 youths with bipolar disorder, more than 30% of their parents had bipolar disorder, but in the families of 30 youths with severe mood dysregulation, fewer than 5% of parents had bipolar disorder (Am J. Psychiatry 2007;164:1238-41).

In recent functional MRI (fMRI) studies, both children with severe mood dysregulation and bipolar disorder had difficulty identifying face emotions, but the brain mechanisms behind their difficulties differed between groups.

"Brain imaging is very much a research tool, but it’s something that we can look forward to in the future as an adjunct in addition to careful clinical assessment, which will always be the hallmark of differential diagnosis," Dr. Leibenluft said.

In one study, children looked at a photo of a neutral face and were asked, "How afraid are you?" and "How wide is the nose?" The 43 children with bipolar disorder and 29 with severe mood dysregulation were significantly more likely to report fear than were the 18 children with nonirritable ADHD and 37 healthy control children. On fMRI during this task, however, only the severe mood dysregulation group showed deactivation in the left amygdala (Am. J. Psychiatry 2010;167:61-9).

At least one prior fMRI study has shown decreased amygdala activation during face emotion processing in patients with major depression (with or without anxiety), compared with patients who have anxiety alone or control patients. "Children with severe mood dysregulation are looking more like depressed children than they are like children with ADHD," Dr. Leibenluft said.

In fMRI studies that will be published soon, both 26 children with bipolar disorder and 22 children with severe mood dysregulation showed deficits in "response reversal" tasks (which would make a person more prone to experience frustration), compared with 34 control children, she said.

In this task, subjects are asked to select between two objects, told that one will win them points and the other will lose them points, and occasionally, the objects will switch roles without announcement. It’s an assessment of one’s ability to adapt to changes in the environment.

"In real life, it would sort of be as if a child is on the playground and then recess is over. The children have to change what they’re doing and adapt to the environment," Dr. Leibenluft said. "You could see how if you [weren’t able to adapt], you would end up extremely frustrated."

The fMRI studies demonstrated that when the control subjects made an error, the right caudate activated, sending them an error signal to rethink what they’re doing; the caudate did not alert the children with bipolar disorder or severe mood dysregulation.

The right inferior frontal gyrus, which plays an important role in attention when adaptation is required, activated in both the control children and those with bipolar disorder when they made an error in the task, but the children with severe mood dysregulation showed much less activation in this area, she said.

Studies will continue to tease out the similarities and differences between bipolar disorder and severe mood dysregulation as distinct categories or part of a spectrum. "This is where, ultimately, far down the line, imaging may be able to complement clinical assessment in differential diagnosis," she said.

Dr. Leibenluft’s research is funded by the National Institutes of Mental Health. The European College of Neuropsychopharmacology paid her expenses to speak at the meeting.