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NEW YORK – Treating children and teens with refractory bipolar disorder requires both persistence and faith, according to Dr. Gabrielle A. Carlson.
Although new data are trickling out, few of the medications available for treating both mania and depression have been extensively studied in children and teens, Dr. Carlson said at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.
"The first-generation antipsychotics have been grandfathered in with [Food and Drug Administration] approval. There are very little data for youngsters, and it’s unlikely that there ever will be, since they are generic now and no one will be spending the money" to further investigate them.
A few pediatric trials are in progress for some of the newer, second-generation antipsychotics, but most efficacy data are still from adult studies, said Dr. Carlson, professor of psychiatry and pediatrics at Stony Brook University, New York.
Most recently, paloperidone was found effective as an acute treatment for mania in children with bipolar disorder. But the open-label study was very small – just 15 patients – and was terminated early because of the slow enrollment. The study tested two doses (3 mg and 12 mg). There was a significant mean decline of almost 19 points on the Young Mania Rating Scale after 8 weeks of treatment. Children gained a mean of 4 pounds, however (Psychopharmacology [Berl.] 2013;227:449-58).
Sublingual treatment
Asenapine "is the new kid on the block," Dr. Carlson said. It was approved in 2009 for the acute treatment of schizophrenia and manic or mixed bipolar episodes in adults. It’s administered as a sublingual tablet that takes about 10 minutes to dissolve.
"This is good news if you’ve got a kid who has trouble swallowing pills. The bad news is that you have to hold it under your tongue for 10 minutes, and if you’ve got an aggressive, agitated kid – well, good luck with that. If he does it, though, you can get a good treatment response pretty quickly, because it has a peak concentration of 30-90 minutes and a half-life of about 24 hours."
The adult studies of asenapine showed a significant benefit in about 1 week, with many bipolar patients seeing a 50% reduction in symptoms. Two placebo-controlled trials in children are just wrapping up. The first, comprising 400 children, is complete, but no data have yet been published.
The second, a 50-week open-label study, is ongoing; about 300 children are enrolled.
In the adult studies of asenapine, the number needed to treat was about eight. "The NNT for many other drugs is four or five, so to me this looks like a contender, but not anything great. The sublingual route is the biggest benefit," although, Dr. Carlson cautioned, "it does make noncompliance a lot easier, just by swallowing it." The bioavailability when swallowed is only about 35%.
Asenapine is sedating, so it might be a good choice for as-needed treatment; the weight gain profile is similar to that of olanzapine. The twice-daily dosing is weight based, Dr. Carlson said. "Younger children are more sensitive to the initial dose, so they need a lower starting point and shorter up-titration, which isn’t necessary in the older kids."
For children with bipolar depression, there’s little evidence to support the use of quetiapine. There are no data in youngsters and few data to support its use in adults. A 2012 meta-analysis found that the drug is no better than placebo.
The combination of olanzapine and fluoxetine has been examined in children aged 10-17 years. The industry-sponsored placebo-controlled study treated 160 children for 8 weeks.
At the end of the study, remission rates were 59% in the active group and 43% in the placebo group – a significant difference. Children taking the combination gained significantly more weight than those taking placebo – an average of 4 vs. 0.5 kg. There were also significant increases in liver enzymes and prolactin in those taking the drugs, as well as a higher chance of prolonged QTc intervals.
Unpublished results of another study hint that lamotrigine also might be effective in children with bipolar depression, Dr. Carlson said.
The 8-week study looked at what happened to children aged 10-17 years who had lamotrigine withdrawn after they had responded to it. These patients were given the option of continuing the drug or switching to placebo.
"So far they have 250 enrolled," Dr. Carlson said. "Of these, 136 were willing to be randomized, meaning that at least 60% got better in the open-label phase."
There are no published pediatric data on lurasidone or ketamine, although both seem promising. Lurasidone has been approved for adults, and a study being done in youngsters is not specific for bipolar disorder. Children with schizophrenia, psychosis, autism disorders, Asperger’s syndrome, and refractory major depressive disorder also can enroll.
A recently published adult study, PREVAIL 2 (Program to Evaluate the Antidepressant Impact of Lurasidone), comprised 505 patients with bipolar I depression. They were randomized to once-daily, flexibly dosed lurasidone at either 20-60 mg/day or 80-120 mg/day, or to placebo.
After 6 weeks, depression scores fell in both the 20- to 60-mg/day group (–15.4; effect size = 0.51) and the 80- to 120-mg/day group (–15.4; effect size =0.51), compared with placebo (–10.7).
Similarly, lurasidone treatment resulted in significantly greater endpoint reduction in Clinical Global Impressions-Bipolar Scale depression severity scores for both the 20- to 60-mg/day group (–1.8; effect size = 0.61) and the 80- to 120-mg/day group (–1.7; effect size = 0.50), compared with placebo (–1.1). Both lurasidone groups also experienced significant improvements compared with placebo in anxiety symptoms, and in patient-reported measures of quality of life and functional impairment. Response rates were 53% for the active group and 30% for the placebo group, with remission rates of 42% vs. 40%.
"The effect size was similar for the high and low doses, about 0.5, which is not terrible," Dr. Carlson said. "Discontinuation rates were fairly low, suggesting that it may be worth pursuing."
The main side effects were nausea, headache, akathisia, and somnolence, but very few changes were found in weight, lipids, or measures of glycemic control.
"Ketamine is something we’ve been hearing a lot about," Dr. Carlson said. "If we can come up with a way to give it that’s not intravenous and make it last for a while, it could be really valuable."
One study found that adults randomized to ketamine had significantly greater improvements in depression scores after 24 hours than did those who had midazolam.
The study comprised 73 patients. Response rates at 24 hours were 64% vs. 28% for placebo – with patients taking ketamine more than twice as likely to respond in the adjusted analysis.
The response was highest in the first 3 days after infusion; by day 7, it had dropped to about 45%. A review also highlighted ketamine's 'Achilles heel' – it just hasn’t got staying power. The paper looked at effect sizes in two depression studies and found that they peaked around 2 or 3 days after infusion. But 2 weeks later, the effect size was just about the same as with placebo.
"It’s a really interesting drug, and it does appear to hold some promise," Dr. Carlson said.
Dr. Carlson noted that she has received research funding from Bristol-Myers Squibb, GlaxoSmithKline, Merck & Co., Otsuka America Pharmaceutical, Pfizer, and Schering-Plough.
NEW YORK – Treating children and teens with refractory bipolar disorder requires both persistence and faith, according to Dr. Gabrielle A. Carlson.
Although new data are trickling out, few of the medications available for treating both mania and depression have been extensively studied in children and teens, Dr. Carlson said at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.
"The first-generation antipsychotics have been grandfathered in with [Food and Drug Administration] approval. There are very little data for youngsters, and it’s unlikely that there ever will be, since they are generic now and no one will be spending the money" to further investigate them.
A few pediatric trials are in progress for some of the newer, second-generation antipsychotics, but most efficacy data are still from adult studies, said Dr. Carlson, professor of psychiatry and pediatrics at Stony Brook University, New York.
Most recently, paloperidone was found effective as an acute treatment for mania in children with bipolar disorder. But the open-label study was very small – just 15 patients – and was terminated early because of the slow enrollment. The study tested two doses (3 mg and 12 mg). There was a significant mean decline of almost 19 points on the Young Mania Rating Scale after 8 weeks of treatment. Children gained a mean of 4 pounds, however (Psychopharmacology [Berl.] 2013;227:449-58).
Sublingual treatment
Asenapine "is the new kid on the block," Dr. Carlson said. It was approved in 2009 for the acute treatment of schizophrenia and manic or mixed bipolar episodes in adults. It’s administered as a sublingual tablet that takes about 10 minutes to dissolve.
"This is good news if you’ve got a kid who has trouble swallowing pills. The bad news is that you have to hold it under your tongue for 10 minutes, and if you’ve got an aggressive, agitated kid – well, good luck with that. If he does it, though, you can get a good treatment response pretty quickly, because it has a peak concentration of 30-90 minutes and a half-life of about 24 hours."
The adult studies of asenapine showed a significant benefit in about 1 week, with many bipolar patients seeing a 50% reduction in symptoms. Two placebo-controlled trials in children are just wrapping up. The first, comprising 400 children, is complete, but no data have yet been published.
The second, a 50-week open-label study, is ongoing; about 300 children are enrolled.
In the adult studies of asenapine, the number needed to treat was about eight. "The NNT for many other drugs is four or five, so to me this looks like a contender, but not anything great. The sublingual route is the biggest benefit," although, Dr. Carlson cautioned, "it does make noncompliance a lot easier, just by swallowing it." The bioavailability when swallowed is only about 35%.
Asenapine is sedating, so it might be a good choice for as-needed treatment; the weight gain profile is similar to that of olanzapine. The twice-daily dosing is weight based, Dr. Carlson said. "Younger children are more sensitive to the initial dose, so they need a lower starting point and shorter up-titration, which isn’t necessary in the older kids."
For children with bipolar depression, there’s little evidence to support the use of quetiapine. There are no data in youngsters and few data to support its use in adults. A 2012 meta-analysis found that the drug is no better than placebo.
The combination of olanzapine and fluoxetine has been examined in children aged 10-17 years. The industry-sponsored placebo-controlled study treated 160 children for 8 weeks.
At the end of the study, remission rates were 59% in the active group and 43% in the placebo group – a significant difference. Children taking the combination gained significantly more weight than those taking placebo – an average of 4 vs. 0.5 kg. There were also significant increases in liver enzymes and prolactin in those taking the drugs, as well as a higher chance of prolonged QTc intervals.
Unpublished results of another study hint that lamotrigine also might be effective in children with bipolar depression, Dr. Carlson said.
The 8-week study looked at what happened to children aged 10-17 years who had lamotrigine withdrawn after they had responded to it. These patients were given the option of continuing the drug or switching to placebo.
"So far they have 250 enrolled," Dr. Carlson said. "Of these, 136 were willing to be randomized, meaning that at least 60% got better in the open-label phase."
There are no published pediatric data on lurasidone or ketamine, although both seem promising. Lurasidone has been approved for adults, and a study being done in youngsters is not specific for bipolar disorder. Children with schizophrenia, psychosis, autism disorders, Asperger’s syndrome, and refractory major depressive disorder also can enroll.
A recently published adult study, PREVAIL 2 (Program to Evaluate the Antidepressant Impact of Lurasidone), comprised 505 patients with bipolar I depression. They were randomized to once-daily, flexibly dosed lurasidone at either 20-60 mg/day or 80-120 mg/day, or to placebo.
After 6 weeks, depression scores fell in both the 20- to 60-mg/day group (–15.4; effect size = 0.51) and the 80- to 120-mg/day group (–15.4; effect size =0.51), compared with placebo (–10.7).
Similarly, lurasidone treatment resulted in significantly greater endpoint reduction in Clinical Global Impressions-Bipolar Scale depression severity scores for both the 20- to 60-mg/day group (–1.8; effect size = 0.61) and the 80- to 120-mg/day group (–1.7; effect size = 0.50), compared with placebo (–1.1). Both lurasidone groups also experienced significant improvements compared with placebo in anxiety symptoms, and in patient-reported measures of quality of life and functional impairment. Response rates were 53% for the active group and 30% for the placebo group, with remission rates of 42% vs. 40%.
"The effect size was similar for the high and low doses, about 0.5, which is not terrible," Dr. Carlson said. "Discontinuation rates were fairly low, suggesting that it may be worth pursuing."
The main side effects were nausea, headache, akathisia, and somnolence, but very few changes were found in weight, lipids, or measures of glycemic control.
"Ketamine is something we’ve been hearing a lot about," Dr. Carlson said. "If we can come up with a way to give it that’s not intravenous and make it last for a while, it could be really valuable."
One study found that adults randomized to ketamine had significantly greater improvements in depression scores after 24 hours than did those who had midazolam.
The study comprised 73 patients. Response rates at 24 hours were 64% vs. 28% for placebo – with patients taking ketamine more than twice as likely to respond in the adjusted analysis.
The response was highest in the first 3 days after infusion; by day 7, it had dropped to about 45%. A review also highlighted ketamine's 'Achilles heel' – it just hasn’t got staying power. The paper looked at effect sizes in two depression studies and found that they peaked around 2 or 3 days after infusion. But 2 weeks later, the effect size was just about the same as with placebo.
"It’s a really interesting drug, and it does appear to hold some promise," Dr. Carlson said.
Dr. Carlson noted that she has received research funding from Bristol-Myers Squibb, GlaxoSmithKline, Merck & Co., Otsuka America Pharmaceutical, Pfizer, and Schering-Plough.
NEW YORK – Treating children and teens with refractory bipolar disorder requires both persistence and faith, according to Dr. Gabrielle A. Carlson.
Although new data are trickling out, few of the medications available for treating both mania and depression have been extensively studied in children and teens, Dr. Carlson said at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.
"The first-generation antipsychotics have been grandfathered in with [Food and Drug Administration] approval. There are very little data for youngsters, and it’s unlikely that there ever will be, since they are generic now and no one will be spending the money" to further investigate them.
A few pediatric trials are in progress for some of the newer, second-generation antipsychotics, but most efficacy data are still from adult studies, said Dr. Carlson, professor of psychiatry and pediatrics at Stony Brook University, New York.
Most recently, paloperidone was found effective as an acute treatment for mania in children with bipolar disorder. But the open-label study was very small – just 15 patients – and was terminated early because of the slow enrollment. The study tested two doses (3 mg and 12 mg). There was a significant mean decline of almost 19 points on the Young Mania Rating Scale after 8 weeks of treatment. Children gained a mean of 4 pounds, however (Psychopharmacology [Berl.] 2013;227:449-58).
Sublingual treatment
Asenapine "is the new kid on the block," Dr. Carlson said. It was approved in 2009 for the acute treatment of schizophrenia and manic or mixed bipolar episodes in adults. It’s administered as a sublingual tablet that takes about 10 minutes to dissolve.
"This is good news if you’ve got a kid who has trouble swallowing pills. The bad news is that you have to hold it under your tongue for 10 minutes, and if you’ve got an aggressive, agitated kid – well, good luck with that. If he does it, though, you can get a good treatment response pretty quickly, because it has a peak concentration of 30-90 minutes and a half-life of about 24 hours."
The adult studies of asenapine showed a significant benefit in about 1 week, with many bipolar patients seeing a 50% reduction in symptoms. Two placebo-controlled trials in children are just wrapping up. The first, comprising 400 children, is complete, but no data have yet been published.
The second, a 50-week open-label study, is ongoing; about 300 children are enrolled.
In the adult studies of asenapine, the number needed to treat was about eight. "The NNT for many other drugs is four or five, so to me this looks like a contender, but not anything great. The sublingual route is the biggest benefit," although, Dr. Carlson cautioned, "it does make noncompliance a lot easier, just by swallowing it." The bioavailability when swallowed is only about 35%.
Asenapine is sedating, so it might be a good choice for as-needed treatment; the weight gain profile is similar to that of olanzapine. The twice-daily dosing is weight based, Dr. Carlson said. "Younger children are more sensitive to the initial dose, so they need a lower starting point and shorter up-titration, which isn’t necessary in the older kids."
For children with bipolar depression, there’s little evidence to support the use of quetiapine. There are no data in youngsters and few data to support its use in adults. A 2012 meta-analysis found that the drug is no better than placebo.
The combination of olanzapine and fluoxetine has been examined in children aged 10-17 years. The industry-sponsored placebo-controlled study treated 160 children for 8 weeks.
At the end of the study, remission rates were 59% in the active group and 43% in the placebo group – a significant difference. Children taking the combination gained significantly more weight than those taking placebo – an average of 4 vs. 0.5 kg. There were also significant increases in liver enzymes and prolactin in those taking the drugs, as well as a higher chance of prolonged QTc intervals.
Unpublished results of another study hint that lamotrigine also might be effective in children with bipolar depression, Dr. Carlson said.
The 8-week study looked at what happened to children aged 10-17 years who had lamotrigine withdrawn after they had responded to it. These patients were given the option of continuing the drug or switching to placebo.
"So far they have 250 enrolled," Dr. Carlson said. "Of these, 136 were willing to be randomized, meaning that at least 60% got better in the open-label phase."
There are no published pediatric data on lurasidone or ketamine, although both seem promising. Lurasidone has been approved for adults, and a study being done in youngsters is not specific for bipolar disorder. Children with schizophrenia, psychosis, autism disorders, Asperger’s syndrome, and refractory major depressive disorder also can enroll.
A recently published adult study, PREVAIL 2 (Program to Evaluate the Antidepressant Impact of Lurasidone), comprised 505 patients with bipolar I depression. They were randomized to once-daily, flexibly dosed lurasidone at either 20-60 mg/day or 80-120 mg/day, or to placebo.
After 6 weeks, depression scores fell in both the 20- to 60-mg/day group (–15.4; effect size = 0.51) and the 80- to 120-mg/day group (–15.4; effect size =0.51), compared with placebo (–10.7).
Similarly, lurasidone treatment resulted in significantly greater endpoint reduction in Clinical Global Impressions-Bipolar Scale depression severity scores for both the 20- to 60-mg/day group (–1.8; effect size = 0.61) and the 80- to 120-mg/day group (–1.7; effect size = 0.50), compared with placebo (–1.1). Both lurasidone groups also experienced significant improvements compared with placebo in anxiety symptoms, and in patient-reported measures of quality of life and functional impairment. Response rates were 53% for the active group and 30% for the placebo group, with remission rates of 42% vs. 40%.
"The effect size was similar for the high and low doses, about 0.5, which is not terrible," Dr. Carlson said. "Discontinuation rates were fairly low, suggesting that it may be worth pursuing."
The main side effects were nausea, headache, akathisia, and somnolence, but very few changes were found in weight, lipids, or measures of glycemic control.
"Ketamine is something we’ve been hearing a lot about," Dr. Carlson said. "If we can come up with a way to give it that’s not intravenous and make it last for a while, it could be really valuable."
One study found that adults randomized to ketamine had significantly greater improvements in depression scores after 24 hours than did those who had midazolam.
The study comprised 73 patients. Response rates at 24 hours were 64% vs. 28% for placebo – with patients taking ketamine more than twice as likely to respond in the adjusted analysis.
The response was highest in the first 3 days after infusion; by day 7, it had dropped to about 45%. A review also highlighted ketamine's 'Achilles heel' – it just hasn’t got staying power. The paper looked at effect sizes in two depression studies and found that they peaked around 2 or 3 days after infusion. But 2 weeks later, the effect size was just about the same as with placebo.
"It’s a really interesting drug, and it does appear to hold some promise," Dr. Carlson said.
Dr. Carlson noted that she has received research funding from Bristol-Myers Squibb, GlaxoSmithKline, Merck & Co., Otsuka America Pharmaceutical, Pfizer, and Schering-Plough.
AT THE PSYCHOPHARMACOLOGY UPDATE INSTITUTE
