Risperidone Tops Lithium, Valproate for Pediatric Acute Mania

BOCA RATON, FLA. – Significantly more children and adolescents with bipolar disorder mania or mixed episodes responded to 8 weeks of treatment with risperidone vs. lithium or valproate in a multicenter, initial monotherapy comparison trial.

At study end, 69% treated with risperidone achieved an "improved" or "much improved" rating on the primary outcome measure, Clinical Global Impressions- –Improvement scale for Mania (CGI-IM). In contrast, 36% of participants taking lithium saw such improvement, as did 24% of the patients taking valproate.

Dr. Karen D. Wagner

"About two-thirds responded to risperidone, one-third to lithium, and about one-quarter to valproate, with no significant difference between lithium and valproate," Dr. Karen D. Wagner said at a meeting of the New Clinical Drug Evaluation Unit (NCDEU) sponsored by the National Institute of Mental Health.

The 290 children enrolled in the Treatment of Early Age Mania (TEAM) study included 93 randomized to risperidone, 93 to lithium, and 104 to valproate. A total 210 completed the 8-week acute treatment trial.

All participants had a bipolar disorder I manic or mixed state episode of 4 weeks or longer. Participants were aged 6-15 years old, making this a younger cohort than the 10-year cutoff used in other, industry-sponsored studies, Dr. Wagner said. The NIMH funds the ongoing TEAM study.

"This was a very impaired group," Dr. Mark A. Riddle said in a separate presentation at the NCDEU meeting. The mean initial onset for mania was at 5.3 years and the mean duration was 4.9 years at study entry, so "these were kids who had really early disorder and really early problems."

In addition, the mean Children’s Global Assessment Scale (CGAS) score at baseline was 39.2; the mean Clinical Global Impressions Scale for Bipolar Disorder (CGI-BP) severity-mania score was 6.0; and the mean K-SADS Mania Rating Scale (KMRS) score was 43.6.

"Childhood bipolar disorder is a chronic illness and can be very impairing at home, school, and [with] peer functioning," said Dr. Riddle, director of the division of child and adolescent psychiatry at Johns Hopkins University, Baltimore. He added that little is known about effective pharmacologic treatment. "TEAM was deemed essential so we can get some sense of children’s response to treatment, which can be different from adults."

What is the best agent to use for a child who has not been on any medications for bipolar disorder? Answering that question was the primary aim of the acute phase of the TEAM study. Led by principal investigator Dr. Barbara Geller, investigators compared the three most-common agents prescribed for mania at the time of enrollment.

"There was nothing special about selection of risperidone, other than there was the most information about use of risperidone in young children," including safety data from autism spectrum disorder populations, said Dr. Wagner, director of the child and adolescent psychiatry division at University of Texas Medical Branch at Galveston.

Most of the children had comorbidities such as attention-deficit/hyperactivity disorder, 92%, and oppositional defiant disorder, 90%. A total 70% also had an anxiety disorder, and 32% had a sleep disorder.

The agents were titrated up over 6 weeks and maintained at the maximum dose for the final 2 weeks. The mean dose/level at study end was 2.6 mg/day risperidone, 1.1 mEq/L lithium, and 114 mcg/mL valproate. "These were reasonable, upward doses," Dr. Wagner said. This strategy used was aimed at avoiding criticism that any unresponsiveness was attributable to insufficient dosing, she added.

Secondary outcome measures also supported a greater efficacy with risperidone. For example, 48% of the risperidone group achieved a CGAS score more than 60, compared with 27% of the lithium group and 17% of the valproate group. Similarly, the final KRMS score indicated that 16% of the risperidone group had mild to minimal residual symptoms, compared with 26% of the lithium group and 28% of the valproate group.

The investigators looked beyond clinical improvements. "We have to weigh side effects with efficacy," Dr. Wagner said.

"Suicidality is always a concern." Seven participants had suicidal behaviors, including two in the risperidone group, three in the lithium group, and two in the valproate group. There were no suicides during the course of study.

"Interestingly, look at suicidal ideation ... it’s in the direction we like to see this go." From baseline to assessment at 8 weeks, there was a significant decrease in suicidal ideation in all groups, Dr. Wagner said. "Remember, this is a very impaired group of children."

The most common side effects included drowsiness in the risperidone group, which increased from 18% at baseline to 51% at 8 weeks; frequent urination, dry mouth, and excessive thirst in the lithium group; and difficulty arousing in the morning in the valproate group. "It was not a surprise that side effects differed. What was possibly more surprising was we did not see a significant change in extrapyramidal effects," Dr. Wagner said.

The was a "pretty significant" increase in body weight in the risperidone group, a mean 3.3 kg, compared with 1.4 kg in the lithium group and 1.7 kg in the valproate group. "Remember this was an 8-week study, Dr. Wagner said.

Anyone who dropped out of the study prior to week 8 was considered a nonresponder. The discontinuation rates were 16% for the risperidone group, 32% for the lithium group, and 26% for the valproate group, for an overall rate of 25%. "This is probably what we see clinically. About 25% of children are no longer on the medication you want them to take by 8 weeks," Dr. Wagner said.

A change of mind led the reasons for discontinuation, cited by 54%. "I’d like to be more definitive about that," Dr. Wagner said. An additional 22% cited side effects, and 10% withdrew because of symptom worsening.

The drug assignment was open and known by everyone except the blinded rater at 8 weeks, a potential limitation of the study, Dr. Riddle said. The large number of participants and allowing 8 weeks for response to monotherapy were strengths of the study.

Dr. Wagner said the TEAM results are comparable with reports from other major studies in the literature. For example, the valproate response rate of 24% in TEAM was exactly the same that Dr. Wagner and her colleagues reported in a divalproex extended-release trial (J. Am. Acad. Child Adolesc. Psychiatry 2009;48:519-32). In addition, the 69% response rate with risperidone was similar to the 58% mean response rate reported among five second-generation atypical medication trials in pediatric populations (Bipolar Disord. 2010;12:116-41).

The next step for TEAM researchers is to delve more deeply into primary and secondary outcomes, Dr. Wagner said. Data analysis from additional measures such as the Children’s Depression Rating Scale–Revised (CDRS-R), the CGI-BP, and the Caregiver Strain Questionnaire (CSQ) are forthcoming.

In addition, "We need to see in the long term if these response rates will continue," Dr. Wagner said.

A second phase of TEAM involves re-randomizing partial responders to a second study medication (the add-on paradigm) or switching nonresponders to one of the other two agents as monotherapy.

Dr. Wagner said she receives honoraria from CMP Medica, Contemporary Forums, Physicians Postgraduate Press, and Quantia Communications. Dr. Riddle said he had no financial disclosures.

BOCA RATON, FLA. – Significantly more children and adolescents with bipolar disorder mania or mixed episodes responded to 8 weeks of treatment with risperidone vs. lithium or valproate in a multicenter, initial monotherapy comparison trial.

At study end, 69% treated with risperidone achieved an "improved" or "much improved" rating on the primary outcome measure, Clinical Global Impressions- –Improvement scale for Mania (CGI-IM). In contrast, 36% of participants taking lithium saw such improvement, as did 24% of the patients taking valproate.

Dr. Karen D. Wagner

"About two-thirds responded to risperidone, one-third to lithium, and about one-quarter to valproate, with no significant difference between lithium and valproate," Dr. Karen D. Wagner said at a meeting of the New Clinical Drug Evaluation Unit (NCDEU) sponsored by the National Institute of Mental Health.

The 290 children enrolled in the Treatment of Early Age Mania (TEAM) study included 93 randomized to risperidone, 93 to lithium, and 104 to valproate. A total 210 completed the 8-week acute treatment trial.

All participants had a bipolar disorder I manic or mixed state episode of 4 weeks or longer. Participants were aged 6-15 years old, making this a younger cohort than the 10-year cutoff used in other, industry-sponsored studies, Dr. Wagner said. The NIMH funds the ongoing TEAM study.

"This was a very impaired group," Dr. Mark A. Riddle said in a separate presentation at the NCDEU meeting. The mean initial onset for mania was at 5.3 years and the mean duration was 4.9 years at study entry, so "these were kids who had really early disorder and really early problems."

In addition, the mean Children’s Global Assessment Scale (CGAS) score at baseline was 39.2; the mean Clinical Global Impressions Scale for Bipolar Disorder (CGI-BP) severity-mania score was 6.0; and the mean K-SADS Mania Rating Scale (KMRS) score was 43.6.

"Childhood bipolar disorder is a chronic illness and can be very impairing at home, school, and [with] peer functioning," said Dr. Riddle, director of the division of child and adolescent psychiatry at Johns Hopkins University, Baltimore. He added that little is known about effective pharmacologic treatment. "TEAM was deemed essential so we can get some sense of children’s response to treatment, which can be different from adults."

What is the best agent to use for a child who has not been on any medications for bipolar disorder? Answering that question was the primary aim of the acute phase of the TEAM study. Led by principal investigator Dr. Barbara Geller, investigators compared the three most-common agents prescribed for mania at the time of enrollment.

"There was nothing special about selection of risperidone, other than there was the most information about use of risperidone in young children," including safety data from autism spectrum disorder populations, said Dr. Wagner, director of the child and adolescent psychiatry division at University of Texas Medical Branch at Galveston.

Most of the children had comorbidities such as attention-deficit/hyperactivity disorder, 92%, and oppositional defiant disorder, 90%. A total 70% also had an anxiety disorder, and 32% had a sleep disorder.

The agents were titrated up over 6 weeks and maintained at the maximum dose for the final 2 weeks. The mean dose/level at study end was 2.6 mg/day risperidone, 1.1 mEq/L lithium, and 114 mcg/mL valproate. "These were reasonable, upward doses," Dr. Wagner said. This strategy used was aimed at avoiding criticism that any unresponsiveness was attributable to insufficient dosing, she added.

Secondary outcome measures also supported a greater efficacy with risperidone. For example, 48% of the risperidone group achieved a CGAS score more than 60, compared with 27% of the lithium group and 17% of the valproate group. Similarly, the final KRMS score indicated that 16% of the risperidone group had mild to minimal residual symptoms, compared with 26% of the lithium group and 28% of the valproate group.

The investigators looked beyond clinical improvements. "We have to weigh side effects with efficacy," Dr. Wagner said.

"Suicidality is always a concern." Seven participants had suicidal behaviors, including two in the risperidone group, three in the lithium group, and two in the valproate group. There were no suicides during the course of study.

"Interestingly, look at suicidal ideation ... it’s in the direction we like to see this go." From baseline to assessment at 8 weeks, there was a significant decrease in suicidal ideation in all groups, Dr. Wagner said. "Remember, this is a very impaired group of children."

The most common side effects included drowsiness in the risperidone group, which increased from 18% at baseline to 51% at 8 weeks; frequent urination, dry mouth, and excessive thirst in the lithium group; and difficulty arousing in the morning in the valproate group. "It was not a surprise that side effects differed. What was possibly more surprising was we did not see a significant change in extrapyramidal effects," Dr. Wagner said.

The was a "pretty significant" increase in body weight in the risperidone group, a mean 3.3 kg, compared with 1.4 kg in the lithium group and 1.7 kg in the valproate group. "Remember this was an 8-week study, Dr. Wagner said.

Anyone who dropped out of the study prior to week 8 was considered a nonresponder. The discontinuation rates were 16% for the risperidone group, 32% for the lithium group, and 26% for the valproate group, for an overall rate of 25%. "This is probably what we see clinically. About 25% of children are no longer on the medication you want them to take by 8 weeks," Dr. Wagner said.

A change of mind led the reasons for discontinuation, cited by 54%. "I’d like to be more definitive about that," Dr. Wagner said. An additional 22% cited side effects, and 10% withdrew because of symptom worsening.

The drug assignment was open and known by everyone except the blinded rater at 8 weeks, a potential limitation of the study, Dr. Riddle said. The large number of participants and allowing 8 weeks for response to monotherapy were strengths of the study.

Dr. Wagner said the TEAM results are comparable with reports from other major studies in the literature. For example, the valproate response rate of 24% in TEAM was exactly the same that Dr. Wagner and her colleagues reported in a divalproex extended-release trial (J. Am. Acad. Child Adolesc. Psychiatry 2009;48:519-32). In addition, the 69% response rate with risperidone was similar to the 58% mean response rate reported among five second-generation atypical medication trials in pediatric populations (Bipolar Disord. 2010;12:116-41).

The next step for TEAM researchers is to delve more deeply into primary and secondary outcomes, Dr. Wagner said. Data analysis from additional measures such as the Children’s Depression Rating Scale–Revised (CDRS-R), the CGI-BP, and the Caregiver Strain Questionnaire (CSQ) are forthcoming.

In addition, "We need to see in the long term if these response rates will continue," Dr. Wagner said.

A second phase of TEAM involves re-randomizing partial responders to a second study medication (the add-on paradigm) or switching nonresponders to one of the other two agents as monotherapy.

Dr. Wagner said she receives honoraria from CMP Medica, Contemporary Forums, Physicians Postgraduate Press, and Quantia Communications. Dr. Riddle said he had no financial disclosures.

BOCA RATON, FLA. – Significantly more children and adolescents with bipolar disorder mania or mixed episodes responded to 8 weeks of treatment with risperidone vs. lithium or valproate in a multicenter, initial monotherapy comparison trial.

At study end, 69% treated with risperidone achieved an "improved" or "much improved" rating on the primary outcome measure, Clinical Global Impressions- –Improvement scale for Mania (CGI-IM). In contrast, 36% of participants taking lithium saw such improvement, as did 24% of the patients taking valproate.

Dr. Karen D. Wagner

"About two-thirds responded to risperidone, one-third to lithium, and about one-quarter to valproate, with no significant difference between lithium and valproate," Dr. Karen D. Wagner said at a meeting of the New Clinical Drug Evaluation Unit (NCDEU) sponsored by the National Institute of Mental Health.

The 290 children enrolled in the Treatment of Early Age Mania (TEAM) study included 93 randomized to risperidone, 93 to lithium, and 104 to valproate. A total 210 completed the 8-week acute treatment trial.

All participants had a bipolar disorder I manic or mixed state episode of 4 weeks or longer. Participants were aged 6-15 years old, making this a younger cohort than the 10-year cutoff used in other, industry-sponsored studies, Dr. Wagner said. The NIMH funds the ongoing TEAM study.

"This was a very impaired group," Dr. Mark A. Riddle said in a separate presentation at the NCDEU meeting. The mean initial onset for mania was at 5.3 years and the mean duration was 4.9 years at study entry, so "these were kids who had really early disorder and really early problems."

In addition, the mean Children’s Global Assessment Scale (CGAS) score at baseline was 39.2; the mean Clinical Global Impressions Scale for Bipolar Disorder (CGI-BP) severity-mania score was 6.0; and the mean K-SADS Mania Rating Scale (KMRS) score was 43.6.

"Childhood bipolar disorder is a chronic illness and can be very impairing at home, school, and [with] peer functioning," said Dr. Riddle, director of the division of child and adolescent psychiatry at Johns Hopkins University, Baltimore. He added that little is known about effective pharmacologic treatment. "TEAM was deemed essential so we can get some sense of children’s response to treatment, which can be different from adults."

What is the best agent to use for a child who has not been on any medications for bipolar disorder? Answering that question was the primary aim of the acute phase of the TEAM study. Led by principal investigator Dr. Barbara Geller, investigators compared the three most-common agents prescribed for mania at the time of enrollment.

"There was nothing special about selection of risperidone, other than there was the most information about use of risperidone in young children," including safety data from autism spectrum disorder populations, said Dr. Wagner, director of the child and adolescent psychiatry division at University of Texas Medical Branch at Galveston.

Most of the children had comorbidities such as attention-deficit/hyperactivity disorder, 92%, and oppositional defiant disorder, 90%. A total 70% also had an anxiety disorder, and 32% had a sleep disorder.

The agents were titrated up over 6 weeks and maintained at the maximum dose for the final 2 weeks. The mean dose/level at study end was 2.6 mg/day risperidone, 1.1 mEq/L lithium, and 114 mcg/mL valproate. "These were reasonable, upward doses," Dr. Wagner said. This strategy used was aimed at avoiding criticism that any unresponsiveness was attributable to insufficient dosing, she added.

Secondary outcome measures also supported a greater efficacy with risperidone. For example, 48% of the risperidone group achieved a CGAS score more than 60, compared with 27% of the lithium group and 17% of the valproate group. Similarly, the final KRMS score indicated that 16% of the risperidone group had mild to minimal residual symptoms, compared with 26% of the lithium group and 28% of the valproate group.

The investigators looked beyond clinical improvements. "We have to weigh side effects with efficacy," Dr. Wagner said.

"Suicidality is always a concern." Seven participants had suicidal behaviors, including two in the risperidone group, three in the lithium group, and two in the valproate group. There were no suicides during the course of study.

"Interestingly, look at suicidal ideation ... it’s in the direction we like to see this go." From baseline to assessment at 8 weeks, there was a significant decrease in suicidal ideation in all groups, Dr. Wagner said. "Remember, this is a very impaired group of children."

The most common side effects included drowsiness in the risperidone group, which increased from 18% at baseline to 51% at 8 weeks; frequent urination, dry mouth, and excessive thirst in the lithium group; and difficulty arousing in the morning in the valproate group. "It was not a surprise that side effects differed. What was possibly more surprising was we did not see a significant change in extrapyramidal effects," Dr. Wagner said.

The was a "pretty significant" increase in body weight in the risperidone group, a mean 3.3 kg, compared with 1.4 kg in the lithium group and 1.7 kg in the valproate group. "Remember this was an 8-week study, Dr. Wagner said.

Anyone who dropped out of the study prior to week 8 was considered a nonresponder. The discontinuation rates were 16% for the risperidone group, 32% for the lithium group, and 26% for the valproate group, for an overall rate of 25%. "This is probably what we see clinically. About 25% of children are no longer on the medication you want them to take by 8 weeks," Dr. Wagner said.

A change of mind led the reasons for discontinuation, cited by 54%. "I’d like to be more definitive about that," Dr. Wagner said. An additional 22% cited side effects, and 10% withdrew because of symptom worsening.

The drug assignment was open and known by everyone except the blinded rater at 8 weeks, a potential limitation of the study, Dr. Riddle said. The large number of participants and allowing 8 weeks for response to monotherapy were strengths of the study.

Dr. Wagner said the TEAM results are comparable with reports from other major studies in the literature. For example, the valproate response rate of 24% in TEAM was exactly the same that Dr. Wagner and her colleagues reported in a divalproex extended-release trial (J. Am. Acad. Child Adolesc. Psychiatry 2009;48:519-32). In addition, the 69% response rate with risperidone was similar to the 58% mean response rate reported among five second-generation atypical medication trials in pediatric populations (Bipolar Disord. 2010;12:116-41).

The next step for TEAM researchers is to delve more deeply into primary and secondary outcomes, Dr. Wagner said. Data analysis from additional measures such as the Children’s Depression Rating Scale–Revised (CDRS-R), the CGI-BP, and the Caregiver Strain Questionnaire (CSQ) are forthcoming.

In addition, "We need to see in the long term if these response rates will continue," Dr. Wagner said.

A second phase of TEAM involves re-randomizing partial responders to a second study medication (the add-on paradigm) or switching nonresponders to one of the other two agents as monotherapy.

Dr. Wagner said she receives honoraria from CMP Medica, Contemporary Forums, Physicians Postgraduate Press, and Quantia Communications. Dr. Riddle said he had no financial disclosures.