Psychopharmacology Update Institute

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.

Michele G. Sullivan/Frontline Medical News

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.

[email protected]

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.

Michele G. Sullivan/Frontline Medical News

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.

[email protected]

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.

Michele G. Sullivan/Frontline Medical News

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.

[email protected]

NEW YORK – A bit of aripiprazole could be just enough to bring down stubborn prolactin levels for a patient who is otherwise responding well to a specific antipsychotic, according to Dr. Harold E. Carlson.

Unlike most antipsychotics, which have antagonistic activity at the dopamine-2 receptors, aripiprazole is a dopamine receptor agonist. As such, it does not have the same dopamine-blocking effect – which allows dopamine to continue regulating prolactin production in the pituitary gland, Dr. Carlson said at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

"This gives it the ability to actually lower prolactin, which is something we can use therapeutically," said Dr. Carlson, chief of the division of endocrinology at Stony Brook (N.Y.) University.

Hyperprolactinemia is a common side effect of many antipsychotic medications. Risperidone, paliperidone, and haloperidol are almost certain to cause it. The easiest way to address this hormonal imbalance is simply by switching to a different antipsychotic, he said. Ziprasidone is less likely to provoke a prolactin increase than the three older medications. Others – in order of decreasing probability – are lurasidone, iloperidone, quetiapine, asenapine, clozapine, and finally, aripiprazole.

But it’s not necessary to measure everyone’s prolactin, he cautioned. Many patients tolerate an increased level with no symptoms at all.

"If things are normal, don’t bother," he said. "It will lead you down the garden path. If you measure it and it’s mildly elevated, then you are committed to monitor it forever."

Having said that, he cautioned, it is important to ask patients about any issues – menses, for example. "If a young lady says she has missed her period, then I measure it." It also is important to perform a pregnancy test, he said.

Unpublished data collected by Dr. Christoph U. Correll show how effectively an antipsychotic switch can modulate prolactin, Dr. Carlson said. Dr. Correll of the Zucker Hillside Hospital, Glen Oaks, N.Y., found that patients who switched from aripiprazole to quetiapine had an increase in prolactin level. Prolactin decreased in those who switched to quetiapine from olanzapine, risperidone, or ziprasidone.

"You can often switch to a great benefit, assuming that the drug you switch to is as beneficial as the one you switched from," Dr. Carlson said. But if the most effective antipsychotic is also one of the big prolactin-increasers, "you’re better off to combine it with another drug like aripiprazole, which will minimize the degree of hyperprolactinemia."

The seminal study of this technique was published in 2007 (Am. J. Psychiatry 2007;164:1404-10).It comprised 56 adults who developed hyperprolactinemia while taking haloperidol. Patients were randomized to stay on haloperidol alone or to add aripiprazole (15 mg/day for 4 weeks followed by 30 mg/day for 8 weeks).

By week 8, 88% of those taking aripiprazole had normal prolactin levels, compared with about 4% of those in the placebo group. Seven of the 11 nonmenstruating women in the study resumed menses. There was no clinically significant interaction of the two medications, and haloperidol serum levels were stable.

Last year, a smaller study looked at augmenting long-acting injectable risperidone with 5 mg/day aripiprazole in patients with hyperprolactinemia (J. Clin. Psychopharmacol. 2013;33:538-41). The open-label trial continued for 3 months.

Of the 13 patients, 12 had a significant decrease in prolactin level by the end of the first month, with two patients reaching normal levels. The decrease was maintained in the eight patients who continued through the end of the study. Again, there were no clinical adverse effects of adding the medication.

While lowering prolactin is generally safe, Dr. Carlson did caution against it in one circumstance – a woman who is trying to breastfeed. "If someone is post partum and trying to nurse, this is not the time to give aripiprazole, because she will have difficulty maintaining milk production."

Dr. Carlson disclosed that he has received research support from numerous pharmaceutical companies.

[email protected]

NEW YORK – A bit of aripiprazole could be just enough to bring down stubborn prolactin levels for a patient who is otherwise responding well to a specific antipsychotic, according to Dr. Harold E. Carlson.

Unlike most antipsychotics, which have antagonistic activity at the dopamine-2 receptors, aripiprazole is a dopamine receptor agonist. As such, it does not have the same dopamine-blocking effect – which allows dopamine to continue regulating prolactin production in the pituitary gland, Dr. Carlson said at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

"This gives it the ability to actually lower prolactin, which is something we can use therapeutically," said Dr. Carlson, chief of the division of endocrinology at Stony Brook (N.Y.) University.

Hyperprolactinemia is a common side effect of many antipsychotic medications. Risperidone, paliperidone, and haloperidol are almost certain to cause it. The easiest way to address this hormonal imbalance is simply by switching to a different antipsychotic, he said. Ziprasidone is less likely to provoke a prolactin increase than the three older medications. Others – in order of decreasing probability – are lurasidone, iloperidone, quetiapine, asenapine, clozapine, and finally, aripiprazole.

But it’s not necessary to measure everyone’s prolactin, he cautioned. Many patients tolerate an increased level with no symptoms at all.

"If things are normal, don’t bother," he said. "It will lead you down the garden path. If you measure it and it’s mildly elevated, then you are committed to monitor it forever."

Having said that, he cautioned, it is important to ask patients about any issues – menses, for example. "If a young lady says she has missed her period, then I measure it." It also is important to perform a pregnancy test, he said.

Unpublished data collected by Dr. Christoph U. Correll show how effectively an antipsychotic switch can modulate prolactin, Dr. Carlson said. Dr. Correll of the Zucker Hillside Hospital, Glen Oaks, N.Y., found that patients who switched from aripiprazole to quetiapine had an increase in prolactin level. Prolactin decreased in those who switched to quetiapine from olanzapine, risperidone, or ziprasidone.

"You can often switch to a great benefit, assuming that the drug you switch to is as beneficial as the one you switched from," Dr. Carlson said. But if the most effective antipsychotic is also one of the big prolactin-increasers, "you’re better off to combine it with another drug like aripiprazole, which will minimize the degree of hyperprolactinemia."

The seminal study of this technique was published in 2007 (Am. J. Psychiatry 2007;164:1404-10).It comprised 56 adults who developed hyperprolactinemia while taking haloperidol. Patients were randomized to stay on haloperidol alone or to add aripiprazole (15 mg/day for 4 weeks followed by 30 mg/day for 8 weeks).

By week 8, 88% of those taking aripiprazole had normal prolactin levels, compared with about 4% of those in the placebo group. Seven of the 11 nonmenstruating women in the study resumed menses. There was no clinically significant interaction of the two medications, and haloperidol serum levels were stable.

Last year, a smaller study looked at augmenting long-acting injectable risperidone with 5 mg/day aripiprazole in patients with hyperprolactinemia (J. Clin. Psychopharmacol. 2013;33:538-41). The open-label trial continued for 3 months.

Of the 13 patients, 12 had a significant decrease in prolactin level by the end of the first month, with two patients reaching normal levels. The decrease was maintained in the eight patients who continued through the end of the study. Again, there were no clinical adverse effects of adding the medication.

While lowering prolactin is generally safe, Dr. Carlson did caution against it in one circumstance – a woman who is trying to breastfeed. "If someone is post partum and trying to nurse, this is not the time to give aripiprazole, because she will have difficulty maintaining milk production."

Dr. Carlson disclosed that he has received research support from numerous pharmaceutical companies.

[email protected]

NEW YORK – A bit of aripiprazole could be just enough to bring down stubborn prolactin levels for a patient who is otherwise responding well to a specific antipsychotic, according to Dr. Harold E. Carlson.

Unlike most antipsychotics, which have antagonistic activity at the dopamine-2 receptors, aripiprazole is a dopamine receptor agonist. As such, it does not have the same dopamine-blocking effect – which allows dopamine to continue regulating prolactin production in the pituitary gland, Dr. Carlson said at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

"This gives it the ability to actually lower prolactin, which is something we can use therapeutically," said Dr. Carlson, chief of the division of endocrinology at Stony Brook (N.Y.) University.

Hyperprolactinemia is a common side effect of many antipsychotic medications. Risperidone, paliperidone, and haloperidol are almost certain to cause it. The easiest way to address this hormonal imbalance is simply by switching to a different antipsychotic, he said. Ziprasidone is less likely to provoke a prolactin increase than the three older medications. Others – in order of decreasing probability – are lurasidone, iloperidone, quetiapine, asenapine, clozapine, and finally, aripiprazole.

But it’s not necessary to measure everyone’s prolactin, he cautioned. Many patients tolerate an increased level with no symptoms at all.

"If things are normal, don’t bother," he said. "It will lead you down the garden path. If you measure it and it’s mildly elevated, then you are committed to monitor it forever."

Having said that, he cautioned, it is important to ask patients about any issues – menses, for example. "If a young lady says she has missed her period, then I measure it." It also is important to perform a pregnancy test, he said.

Unpublished data collected by Dr. Christoph U. Correll show how effectively an antipsychotic switch can modulate prolactin, Dr. Carlson said. Dr. Correll of the Zucker Hillside Hospital, Glen Oaks, N.Y., found that patients who switched from aripiprazole to quetiapine had an increase in prolactin level. Prolactin decreased in those who switched to quetiapine from olanzapine, risperidone, or ziprasidone.

"You can often switch to a great benefit, assuming that the drug you switch to is as beneficial as the one you switched from," Dr. Carlson said. But if the most effective antipsychotic is also one of the big prolactin-increasers, "you’re better off to combine it with another drug like aripiprazole, which will minimize the degree of hyperprolactinemia."

The seminal study of this technique was published in 2007 (Am. J. Psychiatry 2007;164:1404-10).It comprised 56 adults who developed hyperprolactinemia while taking haloperidol. Patients were randomized to stay on haloperidol alone or to add aripiprazole (15 mg/day for 4 weeks followed by 30 mg/day for 8 weeks).

By week 8, 88% of those taking aripiprazole had normal prolactin levels, compared with about 4% of those in the placebo group. Seven of the 11 nonmenstruating women in the study resumed menses. There was no clinically significant interaction of the two medications, and haloperidol serum levels were stable.

Last year, a smaller study looked at augmenting long-acting injectable risperidone with 5 mg/day aripiprazole in patients with hyperprolactinemia (J. Clin. Psychopharmacol. 2013;33:538-41). The open-label trial continued for 3 months.

Of the 13 patients, 12 had a significant decrease in prolactin level by the end of the first month, with two patients reaching normal levels. The decrease was maintained in the eight patients who continued through the end of the study. Again, there were no clinical adverse effects of adding the medication.

While lowering prolactin is generally safe, Dr. Carlson did caution against it in one circumstance – a woman who is trying to breastfeed. "If someone is post partum and trying to nurse, this is not the time to give aripiprazole, because she will have difficulty maintaining milk production."

Dr. Carlson disclosed that he has received research support from numerous pharmaceutical companies.

[email protected]

NEW YORK – Cognitive-behavioral therapy seems to ramp up the beneficial effect of antidepressant treatment for children and teens.

About 60% of youngsters will respond favorably to their first antidepressant medication – generally a selective serotonin reuptake inhibitor (SSRI), Dr. Karen D. Wagner said at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

Switching to a different antidepressant will help about 50% of those who don’t respond. But adding psychotherapy will grab about 10% more – bringing the total response rate up to around 70%, said Dr. Wagner of the University of Texas Medical Branch, Galveston.

The landmark TORDIA (Treatment of Resistant Depression in Adolescents) study showed very clearly that piggybacking both treatments is more effective than using medication alone (JAMA 2008;299:785-92).

The study was published in 2008 but remains a key piece of clinical evidence for helping youngsters with treatment-resistant depression. It included about 300 teens who failed their initial 8-week SSRI therapy. They were then randomized to 12 weeks of switching to a different SSRI alone; switching to venlafaxine alone; or switching to either of the drugs plus cognitive-behavioral therapy (CBT).

Adding CBT to either medication showed a higher response rate (55%) than did the medication alone (40%). The new drugs alone were equally effective (new SSRI, 47%; venlafaxine, 48%).

TORDIA could give the impression that psychotherapy might be the best choice for initial treatment, Dr. Wagner said. While it is a great add-on, the timing of CBT response is a big consideration.

"CBT certainly increases the pool of patients who will respond, but it is not as effective initially as medication. CBT eventually does catch up, but if you have a child with moderate to severe depression, the question is: Do we have the time for that? I tend to encourage parents to think about medication first if we don’t have many months to wait for a child to get well."

Choosing among off-label medications

Venlafaxine is one of many antidepressants that are not approved for use in children and teens. Treating depression in youngsters almost always means off-label prescribing. Only two antidepressants – fluoxetine and escitalopram – are Food and Drug Administration–approved for children and teens, and only fluoxetine is approved for children younger than 12 years. And data are actually mixed about fluoxetine; a recent published study showed it was no different from placebo over 6 months.

Of the older, more well-known antidepressants, only two have positive data for youngsters. One randomized study of citalopram posted positive findings for its primary endpoint (Am. J. Psychiatry 2004;161:1079-83). The other is sertraline, which had positive overall findings in a pooled analysis, although the individual studies were negative (JAMA 2003;290:1033-41).

Studies on all of the other drugs were negative, including mirtazapine (two studies), nefazodone (two), paroxetine (three), and venlafaxine (two). This doesn’t mean the medications won’t work – they do benefit some children, Dr. Wagner said. But parents need to know that the studies in children were not positive. However, she added, the safety profiles were all reasonably good.

There are no pediatric safety or efficacy data on any of the new antidepressants. That list includes vilazodone, desvenlafaxine, levomilnacipran, vortioxetine, as well as the less-traditional choices of l-methylfolate and ketamine.

"When you’re thinking about a treatment algorithm, these should be very, very low on the list," Dr. Wagner said. "And make sure to let parents know there are some safety and efficacy data in adults, but they have never been studied in children or adolescents."

Duloxetine disappoints in latest studies

The newest evidence for duloxetine in youngsters with depression looks lousy.

In two highly anticipated, yet-unpublished, phase III trials, duloxetine and fluoxetine – which is already approved for kids – completely fell apart relative to placebo, Dr. Wagner said.

The studies were both sponsored by Eli Lilly; they comprised a total of about 1,000 children and teens. Both included 10-week acute treatment phases followed by 6-month extensions.

The first study randomized patients to up to 120 mg of duloxetine, up to 40 mg of fluoxetine, or placebo for 10 weeks. After that, those who were taking placebo crossed over to up to 120 mg of duloxetine for 6 months. The other regimens remained stable.

By 10 weeks, the mean decrease in the Children’s Depression Rating Scale was 24.3 points for duloxetine, 23.7 points for fluoxetine, and 24.3 points for placebo. By 36 weeks, the CDRS for children still taking duloxetine had decreased another 7 points. It decreased by an additional 9.9 points in those who continued fluoxetine, and by 9.6 points in those who crossed over to duloxetine. None of the between-group differences were significant.

The second trial compared duloxetine 60 mg followed by up to 120 mg; duloxetine 30 mg followed by up to 120 mg; fluoxetine 20 mg followed by up to 40 mg; and placebo followed by up to 120 mg duloxetine.

At 10 weeks, the CDRS had fallen by 24.6 points in the duloxetine groups, 22.6 points in the fluoxetine group, and 21.6 points in the placebo group.

By 36 weeks, the CDRS had fallen an additional 7.8 points in the 30 mg duloxetine group; 7.4 points in the 60 mg duloxetine group; and 10 points in the fluoxetine group.

"This is really sad news," Dr. Wagner said. "You just couldn’t make these numbers any closer. Based on the results of these two studies, are we going to see duloxetine approved for children and adolescents? No. Will there be more studies done? Perhaps, but they take a long time to do."

However, she stressed, "even though there was no separation from placebo, some children do respond. Duloxetine still could be an okay choice, but parents need to know these studies were negative."

Dr. Wagner has no financial relationships with pharmaceutical companies.

[email protected]

NEW YORK – Cognitive-behavioral therapy seems to ramp up the beneficial effect of antidepressant treatment for children and teens.

About 60% of youngsters will respond favorably to their first antidepressant medication – generally a selective serotonin reuptake inhibitor (SSRI), Dr. Karen D. Wagner said at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

Switching to a different antidepressant will help about 50% of those who don’t respond. But adding psychotherapy will grab about 10% more – bringing the total response rate up to around 70%, said Dr. Wagner of the University of Texas Medical Branch, Galveston.

The landmark TORDIA (Treatment of Resistant Depression in Adolescents) study showed very clearly that piggybacking both treatments is more effective than using medication alone (JAMA 2008;299:785-92).

The study was published in 2008 but remains a key piece of clinical evidence for helping youngsters with treatment-resistant depression. It included about 300 teens who failed their initial 8-week SSRI therapy. They were then randomized to 12 weeks of switching to a different SSRI alone; switching to venlafaxine alone; or switching to either of the drugs plus cognitive-behavioral therapy (CBT).

Adding CBT to either medication showed a higher response rate (55%) than did the medication alone (40%). The new drugs alone were equally effective (new SSRI, 47%; venlafaxine, 48%).

TORDIA could give the impression that psychotherapy might be the best choice for initial treatment, Dr. Wagner said. While it is a great add-on, the timing of CBT response is a big consideration.

"CBT certainly increases the pool of patients who will respond, but it is not as effective initially as medication. CBT eventually does catch up, but if you have a child with moderate to severe depression, the question is: Do we have the time for that? I tend to encourage parents to think about medication first if we don’t have many months to wait for a child to get well."

Choosing among off-label medications

Venlafaxine is one of many antidepressants that are not approved for use in children and teens. Treating depression in youngsters almost always means off-label prescribing. Only two antidepressants – fluoxetine and escitalopram – are Food and Drug Administration–approved for children and teens, and only fluoxetine is approved for children younger than 12 years. And data are actually mixed about fluoxetine; a recent published study showed it was no different from placebo over 6 months.

Of the older, more well-known antidepressants, only two have positive data for youngsters. One randomized study of citalopram posted positive findings for its primary endpoint (Am. J. Psychiatry 2004;161:1079-83). The other is sertraline, which had positive overall findings in a pooled analysis, although the individual studies were negative (JAMA 2003;290:1033-41).

Studies on all of the other drugs were negative, including mirtazapine (two studies), nefazodone (two), paroxetine (three), and venlafaxine (two). This doesn’t mean the medications won’t work – they do benefit some children, Dr. Wagner said. But parents need to know that the studies in children were not positive. However, she added, the safety profiles were all reasonably good.

There are no pediatric safety or efficacy data on any of the new antidepressants. That list includes vilazodone, desvenlafaxine, levomilnacipran, vortioxetine, as well as the less-traditional choices of l-methylfolate and ketamine.

"When you’re thinking about a treatment algorithm, these should be very, very low on the list," Dr. Wagner said. "And make sure to let parents know there are some safety and efficacy data in adults, but they have never been studied in children or adolescents."

Duloxetine disappoints in latest studies

The newest evidence for duloxetine in youngsters with depression looks lousy.

In two highly anticipated, yet-unpublished, phase III trials, duloxetine and fluoxetine – which is already approved for kids – completely fell apart relative to placebo, Dr. Wagner said.

The studies were both sponsored by Eli Lilly; they comprised a total of about 1,000 children and teens. Both included 10-week acute treatment phases followed by 6-month extensions.

The first study randomized patients to up to 120 mg of duloxetine, up to 40 mg of fluoxetine, or placebo for 10 weeks. After that, those who were taking placebo crossed over to up to 120 mg of duloxetine for 6 months. The other regimens remained stable.

By 10 weeks, the mean decrease in the Children’s Depression Rating Scale was 24.3 points for duloxetine, 23.7 points for fluoxetine, and 24.3 points for placebo. By 36 weeks, the CDRS for children still taking duloxetine had decreased another 7 points. It decreased by an additional 9.9 points in those who continued fluoxetine, and by 9.6 points in those who crossed over to duloxetine. None of the between-group differences were significant.

The second trial compared duloxetine 60 mg followed by up to 120 mg; duloxetine 30 mg followed by up to 120 mg; fluoxetine 20 mg followed by up to 40 mg; and placebo followed by up to 120 mg duloxetine.

At 10 weeks, the CDRS had fallen by 24.6 points in the duloxetine groups, 22.6 points in the fluoxetine group, and 21.6 points in the placebo group.

By 36 weeks, the CDRS had fallen an additional 7.8 points in the 30 mg duloxetine group; 7.4 points in the 60 mg duloxetine group; and 10 points in the fluoxetine group.

"This is really sad news," Dr. Wagner said. "You just couldn’t make these numbers any closer. Based on the results of these two studies, are we going to see duloxetine approved for children and adolescents? No. Will there be more studies done? Perhaps, but they take a long time to do."

However, she stressed, "even though there was no separation from placebo, some children do respond. Duloxetine still could be an okay choice, but parents need to know these studies were negative."

Dr. Wagner has no financial relationships with pharmaceutical companies.

[email protected]

NEW YORK – Cognitive-behavioral therapy seems to ramp up the beneficial effect of antidepressant treatment for children and teens.

About 60% of youngsters will respond favorably to their first antidepressant medication – generally a selective serotonin reuptake inhibitor (SSRI), Dr. Karen D. Wagner said at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

Switching to a different antidepressant will help about 50% of those who don’t respond. But adding psychotherapy will grab about 10% more – bringing the total response rate up to around 70%, said Dr. Wagner of the University of Texas Medical Branch, Galveston.

The landmark TORDIA (Treatment of Resistant Depression in Adolescents) study showed very clearly that piggybacking both treatments is more effective than using medication alone (JAMA 2008;299:785-92).

The study was published in 2008 but remains a key piece of clinical evidence for helping youngsters with treatment-resistant depression. It included about 300 teens who failed their initial 8-week SSRI therapy. They were then randomized to 12 weeks of switching to a different SSRI alone; switching to venlafaxine alone; or switching to either of the drugs plus cognitive-behavioral therapy (CBT).

Adding CBT to either medication showed a higher response rate (55%) than did the medication alone (40%). The new drugs alone were equally effective (new SSRI, 47%; venlafaxine, 48%).

TORDIA could give the impression that psychotherapy might be the best choice for initial treatment, Dr. Wagner said. While it is a great add-on, the timing of CBT response is a big consideration.

"CBT certainly increases the pool of patients who will respond, but it is not as effective initially as medication. CBT eventually does catch up, but if you have a child with moderate to severe depression, the question is: Do we have the time for that? I tend to encourage parents to think about medication first if we don’t have many months to wait for a child to get well."

Choosing among off-label medications

Venlafaxine is one of many antidepressants that are not approved for use in children and teens. Treating depression in youngsters almost always means off-label prescribing. Only two antidepressants – fluoxetine and escitalopram – are Food and Drug Administration–approved for children and teens, and only fluoxetine is approved for children younger than 12 years. And data are actually mixed about fluoxetine; a recent published study showed it was no different from placebo over 6 months.

Of the older, more well-known antidepressants, only two have positive data for youngsters. One randomized study of citalopram posted positive findings for its primary endpoint (Am. J. Psychiatry 2004;161:1079-83). The other is sertraline, which had positive overall findings in a pooled analysis, although the individual studies were negative (JAMA 2003;290:1033-41).

Studies on all of the other drugs were negative, including mirtazapine (two studies), nefazodone (two), paroxetine (three), and venlafaxine (two). This doesn’t mean the medications won’t work – they do benefit some children, Dr. Wagner said. But parents need to know that the studies in children were not positive. However, she added, the safety profiles were all reasonably good.

There are no pediatric safety or efficacy data on any of the new antidepressants. That list includes vilazodone, desvenlafaxine, levomilnacipran, vortioxetine, as well as the less-traditional choices of l-methylfolate and ketamine.

"When you’re thinking about a treatment algorithm, these should be very, very low on the list," Dr. Wagner said. "And make sure to let parents know there are some safety and efficacy data in adults, but they have never been studied in children or adolescents."

Duloxetine disappoints in latest studies

The newest evidence for duloxetine in youngsters with depression looks lousy.

In two highly anticipated, yet-unpublished, phase III trials, duloxetine and fluoxetine – which is already approved for kids – completely fell apart relative to placebo, Dr. Wagner said.

The studies were both sponsored by Eli Lilly; they comprised a total of about 1,000 children and teens. Both included 10-week acute treatment phases followed by 6-month extensions.

The first study randomized patients to up to 120 mg of duloxetine, up to 40 mg of fluoxetine, or placebo for 10 weeks. After that, those who were taking placebo crossed over to up to 120 mg of duloxetine for 6 months. The other regimens remained stable.

By 10 weeks, the mean decrease in the Children’s Depression Rating Scale was 24.3 points for duloxetine, 23.7 points for fluoxetine, and 24.3 points for placebo. By 36 weeks, the CDRS for children still taking duloxetine had decreased another 7 points. It decreased by an additional 9.9 points in those who continued fluoxetine, and by 9.6 points in those who crossed over to duloxetine. None of the between-group differences were significant.

The second trial compared duloxetine 60 mg followed by up to 120 mg; duloxetine 30 mg followed by up to 120 mg; fluoxetine 20 mg followed by up to 40 mg; and placebo followed by up to 120 mg duloxetine.

At 10 weeks, the CDRS had fallen by 24.6 points in the duloxetine groups, 22.6 points in the fluoxetine group, and 21.6 points in the placebo group.

By 36 weeks, the CDRS had fallen an additional 7.8 points in the 30 mg duloxetine group; 7.4 points in the 60 mg duloxetine group; and 10 points in the fluoxetine group.

"This is really sad news," Dr. Wagner said. "You just couldn’t make these numbers any closer. Based on the results of these two studies, are we going to see duloxetine approved for children and adolescents? No. Will there be more studies done? Perhaps, but they take a long time to do."

However, she stressed, "even though there was no separation from placebo, some children do respond. Duloxetine still could be an okay choice, but parents need to know these studies were negative."

Dr. Wagner has no financial relationships with pharmaceutical companies.

[email protected]

NEW YORK – Effectively managing children with refractory anxiety disorders isn’t easy – and decisions made during treatment can set the tone for a lifetime, according to Dr. John T. Walkup.

"It’s really hard to medicate kids," Dr. Walkup said at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry. "It takes a lot of work, a lot of time, and a lot of persuasion and convincing. Sometimes the family is resistant, so we just don’t put in the effort to make it happen. And these kids will sputter and not do very well."

That’s a shame, said Dr. Walkup, a child psychiatrist at New York Presbyterian Hospital, because pediatric anxiety can respond very well to the right treatment. But if children are left to flounder, the risk of long-term disengagement is very high.

"Many times adult psychiatric disorders start in childhood. If we fumble the first couple of attempts at treatment, this is a youngster who may grow into adulthood with no confidence in psychiatric care."

Dr. Walkup said he often sees patients labeled as refractory, who simply haven’t been appropriately treated. A common problem is having no real plan for reaching a goal. "I hear clinicians say, ‘Let’s just start at this dose and see how it goes.’ I guarantee if you don’t know where you’re going, you’re not going to go anywhere."

The "start low, go slow" method can be problematic if the dose never gets high enough.

"We want to be cautious, and we don’t want to do harm, but there’s a potential problem here. You can build treatment nihilism in the family. Because while you think you’re being prudent and thoughtful, the patient and family think: ‘I’m taking this thing and not getting better. Who is this person, and why should I trust him?’ "

Suicidality is a legitimate concern, but a very rare occurrence. According to the National Institutes of Health, Dr. Walkup said, the number needed to harm for suicidality is around 143. "If you examine that further, most of those are not deaths or attempts, but increased or new ideation."

Activation happens with some children on selective serotonin reuptake inhibitors. It’s extremely uncomfortable for patients and families, but usually occurs at low doses, is transient, and almost always has nothing to do with the long-term prognosis. Activation is sometimes misidentified as bipolar switching to mania, which is actually very rare. Of the 12% of treated children who experience activation, just 1% become manic.

When SSRIs are associated with activation severe enough to switch drugs, "I like mirtazapine," Dr. Walkup said. "It comes in an orally disintegrating tablet, which is good for kids who can’t swallow pills. It’s sedating, so it helps anxious kids sleep. And anxious undereaters who take it sometimes begin to chow down a little."

Switching to or adding another drug is a balancing act that, if not done carefully, can result in symptom resurgence. "The traditional switching strategy is to discontinue the first med and wait for it to clear and then start the second. During that period, children can have a return of symptoms, so this is not something you want to do when the kid is at summer camp, or over a winter holiday.

"I actually don’t do it that way any more," he added. "I prefer a cross-taper."

A common mistake in cross-tapering is, again, stopping the old medication too soon – before the second one has had a chance to kick in. "People get uncomfortable with having two drugs on board. It’s not for the faint of heart, but you have to keep on with the first one until you have a sense that the second one is going to work."

Sometimes luck kicks in, too. "I have experienced a few times – and sometimes hoped for– a kind of augmentation response. The child has an abrupt improvement with the addition of the new drug. When people see this, it can free them up to discontinue the old one, again too early. The problem here is that the old drug is the substrate that the new one is working on.

"If I have a patient who does get better like this, I just leave him on the two meds. Sometimes the improvement is very brisk, and it can really bring families into the fold with using medication."

Dr. Walkup said he had no relevant financial disclosures.

[email protected]

On Twitter @alz_gal

NEW YORK – Effectively managing children with refractory anxiety disorders isn’t easy – and decisions made during treatment can set the tone for a lifetime, according to Dr. John T. Walkup.

"It’s really hard to medicate kids," Dr. Walkup said at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry. "It takes a lot of work, a lot of time, and a lot of persuasion and convincing. Sometimes the family is resistant, so we just don’t put in the effort to make it happen. And these kids will sputter and not do very well."

That’s a shame, said Dr. Walkup, a child psychiatrist at New York Presbyterian Hospital, because pediatric anxiety can respond very well to the right treatment. But if children are left to flounder, the risk of long-term disengagement is very high.

"Many times adult psychiatric disorders start in childhood. If we fumble the first couple of attempts at treatment, this is a youngster who may grow into adulthood with no confidence in psychiatric care."

Dr. Walkup said he often sees patients labeled as refractory, who simply haven’t been appropriately treated. A common problem is having no real plan for reaching a goal. "I hear clinicians say, ‘Let’s just start at this dose and see how it goes.’ I guarantee if you don’t know where you’re going, you’re not going to go anywhere."

The "start low, go slow" method can be problematic if the dose never gets high enough.

"We want to be cautious, and we don’t want to do harm, but there’s a potential problem here. You can build treatment nihilism in the family. Because while you think you’re being prudent and thoughtful, the patient and family think: ‘I’m taking this thing and not getting better. Who is this person, and why should I trust him?’ "

Suicidality is a legitimate concern, but a very rare occurrence. According to the National Institutes of Health, Dr. Walkup said, the number needed to harm for suicidality is around 143. "If you examine that further, most of those are not deaths or attempts, but increased or new ideation."

Activation happens with some children on selective serotonin reuptake inhibitors. It’s extremely uncomfortable for patients and families, but usually occurs at low doses, is transient, and almost always has nothing to do with the long-term prognosis. Activation is sometimes misidentified as bipolar switching to mania, which is actually very rare. Of the 12% of treated children who experience activation, just 1% become manic.

When SSRIs are associated with activation severe enough to switch drugs, "I like mirtazapine," Dr. Walkup said. "It comes in an orally disintegrating tablet, which is good for kids who can’t swallow pills. It’s sedating, so it helps anxious kids sleep. And anxious undereaters who take it sometimes begin to chow down a little."

Switching to or adding another drug is a balancing act that, if not done carefully, can result in symptom resurgence. "The traditional switching strategy is to discontinue the first med and wait for it to clear and then start the second. During that period, children can have a return of symptoms, so this is not something you want to do when the kid is at summer camp, or over a winter holiday.

"I actually don’t do it that way any more," he added. "I prefer a cross-taper."

A common mistake in cross-tapering is, again, stopping the old medication too soon – before the second one has had a chance to kick in. "People get uncomfortable with having two drugs on board. It’s not for the faint of heart, but you have to keep on with the first one until you have a sense that the second one is going to work."

Sometimes luck kicks in, too. "I have experienced a few times – and sometimes hoped for– a kind of augmentation response. The child has an abrupt improvement with the addition of the new drug. When people see this, it can free them up to discontinue the old one, again too early. The problem here is that the old drug is the substrate that the new one is working on.

"If I have a patient who does get better like this, I just leave him on the two meds. Sometimes the improvement is very brisk, and it can really bring families into the fold with using medication."

Dr. Walkup said he had no relevant financial disclosures.

[email protected]

On Twitter @alz_gal

NEW YORK – Effectively managing children with refractory anxiety disorders isn’t easy – and decisions made during treatment can set the tone for a lifetime, according to Dr. John T. Walkup.

"It’s really hard to medicate kids," Dr. Walkup said at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry. "It takes a lot of work, a lot of time, and a lot of persuasion and convincing. Sometimes the family is resistant, so we just don’t put in the effort to make it happen. And these kids will sputter and not do very well."

That’s a shame, said Dr. Walkup, a child psychiatrist at New York Presbyterian Hospital, because pediatric anxiety can respond very well to the right treatment. But if children are left to flounder, the risk of long-term disengagement is very high.

"Many times adult psychiatric disorders start in childhood. If we fumble the first couple of attempts at treatment, this is a youngster who may grow into adulthood with no confidence in psychiatric care."

Dr. Walkup said he often sees patients labeled as refractory, who simply haven’t been appropriately treated. A common problem is having no real plan for reaching a goal. "I hear clinicians say, ‘Let’s just start at this dose and see how it goes.’ I guarantee if you don’t know where you’re going, you’re not going to go anywhere."

The "start low, go slow" method can be problematic if the dose never gets high enough.

"We want to be cautious, and we don’t want to do harm, but there’s a potential problem here. You can build treatment nihilism in the family. Because while you think you’re being prudent and thoughtful, the patient and family think: ‘I’m taking this thing and not getting better. Who is this person, and why should I trust him?’ "

Suicidality is a legitimate concern, but a very rare occurrence. According to the National Institutes of Health, Dr. Walkup said, the number needed to harm for suicidality is around 143. "If you examine that further, most of those are not deaths or attempts, but increased or new ideation."

Activation happens with some children on selective serotonin reuptake inhibitors. It’s extremely uncomfortable for patients and families, but usually occurs at low doses, is transient, and almost always has nothing to do with the long-term prognosis. Activation is sometimes misidentified as bipolar switching to mania, which is actually very rare. Of the 12% of treated children who experience activation, just 1% become manic.

When SSRIs are associated with activation severe enough to switch drugs, "I like mirtazapine," Dr. Walkup said. "It comes in an orally disintegrating tablet, which is good for kids who can’t swallow pills. It’s sedating, so it helps anxious kids sleep. And anxious undereaters who take it sometimes begin to chow down a little."

Switching to or adding another drug is a balancing act that, if not done carefully, can result in symptom resurgence. "The traditional switching strategy is to discontinue the first med and wait for it to clear and then start the second. During that period, children can have a return of symptoms, so this is not something you want to do when the kid is at summer camp, or over a winter holiday.

"I actually don’t do it that way any more," he added. "I prefer a cross-taper."

A common mistake in cross-tapering is, again, stopping the old medication too soon – before the second one has had a chance to kick in. "People get uncomfortable with having two drugs on board. It’s not for the faint of heart, but you have to keep on with the first one until you have a sense that the second one is going to work."

Sometimes luck kicks in, too. "I have experienced a few times – and sometimes hoped for– a kind of augmentation response. The child has an abrupt improvement with the addition of the new drug. When people see this, it can free them up to discontinue the old one, again too early. The problem here is that the old drug is the substrate that the new one is working on.

"If I have a patient who does get better like this, I just leave him on the two meds. Sometimes the improvement is very brisk, and it can really bring families into the fold with using medication."

Dr. Walkup said he had no relevant financial disclosures.

[email protected]

On Twitter @alz_gal

NEW YORK – Behavioral therapy is generally a more effective way than prescribing medications to help children with trichotillomania – especially if the symptoms are not too severe.

While adults with the disorder seem to improve with some antidepressants and neuroleptics, children and teens do not reap nearly the same benefit, Dr. Barbara J. Coffey said at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

"A lovely randomized study showed that even little children did very well with behavioral therapy," said Dr. Coffey, director of the Institute for Tourette and Tic Disorders at New York University Langone Medical Center. "The concern was that they might not respond as well as [with] older children but, in fact, they did – and maybe even did a little bit better."

Treatment decisions should be based on symptom severity, she said. A couple of scales have been created to assess that in youngsters, including the Trichotillomania Scale for Children. It characterizes symptoms according to both distress and impairment (interference with relationships, school, and grooming routines) and severity (frequency, duration, number of hairs pulled, and controllability).

The Massachusetts General Hospital Hairpulling Scale is a seven-item self-report with a severity rating of 0-4. The Milwaukee Inventory for Styles of Trichotillomania–Child Version is another self-report, this one containing 36 items. The U.S. National Institute of Mental Health Trichotillomania Severity Scale, however, might be the most useful for small children. This tool, which contains a semistructured interview, also is used as an assessment tool in many clinical trials.

For children with mild symptoms, without distress or impairment, "simple behavioral interventions and monitoring may be all that’s needed," Dr. Coffey said.

This includes using strategies that make it just a little harder to physically grasp and pull hairs, such as placing small Band-Aids on fingertips, wearing gloves, or putting on a hat. Parents can help by making sure that the interventions are consistent and giving lots of praise when the child abstains from pulling.

For moderate symptoms, habit reversal therapy is a better choice. "The first few days of treatment are designed to help the child develop an awareness of the circumstances and triggers for pulling, and the sensations or urges that are involved," she said. "We are trying to develop an awareness of the premonitory urge."

The second phase of therapy focuses on developing competing behaviors. "We want them to engage in a behavior that is physically incompatible with pulling – like making a fist, playing with a stress ball, or sitting on their hands. They’re instructed to do this behavior for 1 full minute, so they can learn to tolerate the uncomfortable sensation that drives them to pull."

If the symptoms do not improve, or if they get worse, medication might be looked at as an add-on treatment. The first choice is usually an antidepressant or a neuroleptic, Dr. Coffey said.

Clomipramine probably have a little more positive data behind it than do selective serotonin reuptake inhibitors (SSRIs). A 2007 meta-analysis examined seven studies that included 157 adults who were treated with clomipramine, SSRIs, and behavioral interventions. "Habit reversal therapy was superior to clomipramine. Clomipramine was superior to placebo and to SSRIs. But SSRIs were not superior to placebo. So our usual toolbox of medications that we might use for an obsessive compulsive disorder failed to show efficacy."

Since behavioral therapy is more effective than medical therapy, it is very important to keep these strategies on board when adding any drugs, Dr. Coffey stressed.

N-acetylcysteine, a glutamate modulator, also is being used as an add-on treatment. A few studies have suggested a benefit, but the most recent, published last year, was "a big disappointment," she said. That study randomized 39 children aged 8-17 years to the compound or to placebo for 12 weeks (J. Am Acad. Child Adolesc. Psychiatry 2013;52:231-40).

"The good news is that both groups improved, and there were no real adverse effects," she said. "The bad news is that while both groups improved, there was no significant difference between the active and the placebo groups."

N-acetylcysteine reduces glutamate in glial cells and synapses, and promotes the production of glutathione, the body’s most powerful antioxidant. In adults, it’s been shown to benefit people who have addictions to cocaine and other drugs that activate opioid receptors.

"I still do use it sometimes," Dr. Coffey said. "I believe there are some children who are helped by it." She said the medication is over the counter and has virtually no side effects.

Dr. Coffey disclosed that she is on the advisory boards of Eli Lilly, Jazz Pharmaceuticals, and Novartis. She has received research support from Boehringer Ingelheim, Bristol-Myers Squibb, CatalystPharma, Eli Lilly, Otsuka Pharmaceutical, and Shire. She is on the speakers bureau for Quintiles.

[email protected]

NEW YORK – Behavioral therapy is generally a more effective way than prescribing medications to help children with trichotillomania – especially if the symptoms are not too severe.

While adults with the disorder seem to improve with some antidepressants and neuroleptics, children and teens do not reap nearly the same benefit, Dr. Barbara J. Coffey said at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

"A lovely randomized study showed that even little children did very well with behavioral therapy," said Dr. Coffey, director of the Institute for Tourette and Tic Disorders at New York University Langone Medical Center. "The concern was that they might not respond as well as [with] older children but, in fact, they did – and maybe even did a little bit better."

Treatment decisions should be based on symptom severity, she said. A couple of scales have been created to assess that in youngsters, including the Trichotillomania Scale for Children. It characterizes symptoms according to both distress and impairment (interference with relationships, school, and grooming routines) and severity (frequency, duration, number of hairs pulled, and controllability).

The Massachusetts General Hospital Hairpulling Scale is a seven-item self-report with a severity rating of 0-4. The Milwaukee Inventory for Styles of Trichotillomania–Child Version is another self-report, this one containing 36 items. The U.S. National Institute of Mental Health Trichotillomania Severity Scale, however, might be the most useful for small children. This tool, which contains a semistructured interview, also is used as an assessment tool in many clinical trials.

For children with mild symptoms, without distress or impairment, "simple behavioral interventions and monitoring may be all that’s needed," Dr. Coffey said.

This includes using strategies that make it just a little harder to physically grasp and pull hairs, such as placing small Band-Aids on fingertips, wearing gloves, or putting on a hat. Parents can help by making sure that the interventions are consistent and giving lots of praise when the child abstains from pulling.

For moderate symptoms, habit reversal therapy is a better choice. "The first few days of treatment are designed to help the child develop an awareness of the circumstances and triggers for pulling, and the sensations or urges that are involved," she said. "We are trying to develop an awareness of the premonitory urge."

The second phase of therapy focuses on developing competing behaviors. "We want them to engage in a behavior that is physically incompatible with pulling – like making a fist, playing with a stress ball, or sitting on their hands. They’re instructed to do this behavior for 1 full minute, so they can learn to tolerate the uncomfortable sensation that drives them to pull."

If the symptoms do not improve, or if they get worse, medication might be looked at as an add-on treatment. The first choice is usually an antidepressant or a neuroleptic, Dr. Coffey said.

Clomipramine probably have a little more positive data behind it than do selective serotonin reuptake inhibitors (SSRIs). A 2007 meta-analysis examined seven studies that included 157 adults who were treated with clomipramine, SSRIs, and behavioral interventions. "Habit reversal therapy was superior to clomipramine. Clomipramine was superior to placebo and to SSRIs. But SSRIs were not superior to placebo. So our usual toolbox of medications that we might use for an obsessive compulsive disorder failed to show efficacy."

Since behavioral therapy is more effective than medical therapy, it is very important to keep these strategies on board when adding any drugs, Dr. Coffey stressed.

N-acetylcysteine, a glutamate modulator, also is being used as an add-on treatment. A few studies have suggested a benefit, but the most recent, published last year, was "a big disappointment," she said. That study randomized 39 children aged 8-17 years to the compound or to placebo for 12 weeks (J. Am Acad. Child Adolesc. Psychiatry 2013;52:231-40).

"The good news is that both groups improved, and there were no real adverse effects," she said. "The bad news is that while both groups improved, there was no significant difference between the active and the placebo groups."

N-acetylcysteine reduces glutamate in glial cells and synapses, and promotes the production of glutathione, the body’s most powerful antioxidant. In adults, it’s been shown to benefit people who have addictions to cocaine and other drugs that activate opioid receptors.

"I still do use it sometimes," Dr. Coffey said. "I believe there are some children who are helped by it." She said the medication is over the counter and has virtually no side effects.

Dr. Coffey disclosed that she is on the advisory boards of Eli Lilly, Jazz Pharmaceuticals, and Novartis. She has received research support from Boehringer Ingelheim, Bristol-Myers Squibb, CatalystPharma, Eli Lilly, Otsuka Pharmaceutical, and Shire. She is on the speakers bureau for Quintiles.

[email protected]

NEW YORK – Behavioral therapy is generally a more effective way than prescribing medications to help children with trichotillomania – especially if the symptoms are not too severe.

While adults with the disorder seem to improve with some antidepressants and neuroleptics, children and teens do not reap nearly the same benefit, Dr. Barbara J. Coffey said at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

"A lovely randomized study showed that even little children did very well with behavioral therapy," said Dr. Coffey, director of the Institute for Tourette and Tic Disorders at New York University Langone Medical Center. "The concern was that they might not respond as well as [with] older children but, in fact, they did – and maybe even did a little bit better."

Treatment decisions should be based on symptom severity, she said. A couple of scales have been created to assess that in youngsters, including the Trichotillomania Scale for Children. It characterizes symptoms according to both distress and impairment (interference with relationships, school, and grooming routines) and severity (frequency, duration, number of hairs pulled, and controllability).

The Massachusetts General Hospital Hairpulling Scale is a seven-item self-report with a severity rating of 0-4. The Milwaukee Inventory for Styles of Trichotillomania–Child Version is another self-report, this one containing 36 items. The U.S. National Institute of Mental Health Trichotillomania Severity Scale, however, might be the most useful for small children. This tool, which contains a semistructured interview, also is used as an assessment tool in many clinical trials.

For children with mild symptoms, without distress or impairment, "simple behavioral interventions and monitoring may be all that’s needed," Dr. Coffey said.

This includes using strategies that make it just a little harder to physically grasp and pull hairs, such as placing small Band-Aids on fingertips, wearing gloves, or putting on a hat. Parents can help by making sure that the interventions are consistent and giving lots of praise when the child abstains from pulling.

For moderate symptoms, habit reversal therapy is a better choice. "The first few days of treatment are designed to help the child develop an awareness of the circumstances and triggers for pulling, and the sensations or urges that are involved," she said. "We are trying to develop an awareness of the premonitory urge."

The second phase of therapy focuses on developing competing behaviors. "We want them to engage in a behavior that is physically incompatible with pulling – like making a fist, playing with a stress ball, or sitting on their hands. They’re instructed to do this behavior for 1 full minute, so they can learn to tolerate the uncomfortable sensation that drives them to pull."

If the symptoms do not improve, or if they get worse, medication might be looked at as an add-on treatment. The first choice is usually an antidepressant or a neuroleptic, Dr. Coffey said.

Clomipramine probably have a little more positive data behind it than do selective serotonin reuptake inhibitors (SSRIs). A 2007 meta-analysis examined seven studies that included 157 adults who were treated with clomipramine, SSRIs, and behavioral interventions. "Habit reversal therapy was superior to clomipramine. Clomipramine was superior to placebo and to SSRIs. But SSRIs were not superior to placebo. So our usual toolbox of medications that we might use for an obsessive compulsive disorder failed to show efficacy."

Since behavioral therapy is more effective than medical therapy, it is very important to keep these strategies on board when adding any drugs, Dr. Coffey stressed.

N-acetylcysteine, a glutamate modulator, also is being used as an add-on treatment. A few studies have suggested a benefit, but the most recent, published last year, was "a big disappointment," she said. That study randomized 39 children aged 8-17 years to the compound or to placebo for 12 weeks (J. Am Acad. Child Adolesc. Psychiatry 2013;52:231-40).

"The good news is that both groups improved, and there were no real adverse effects," she said. "The bad news is that while both groups improved, there was no significant difference between the active and the placebo groups."

N-acetylcysteine reduces glutamate in glial cells and synapses, and promotes the production of glutathione, the body’s most powerful antioxidant. In adults, it’s been shown to benefit people who have addictions to cocaine and other drugs that activate opioid receptors.

"I still do use it sometimes," Dr. Coffey said. "I believe there are some children who are helped by it." She said the medication is over the counter and has virtually no side effects.

Dr. Coffey disclosed that she is on the advisory boards of Eli Lilly, Jazz Pharmaceuticals, and Novartis. She has received research support from Boehringer Ingelheim, Bristol-Myers Squibb, CatalystPharma, Eli Lilly, Otsuka Pharmaceutical, and Shire. She is on the speakers bureau for Quintiles.

[email protected]

NEW YORK – Neither approved nor investigational drugs seem to have much of an effect on the core symptoms of autism.

Medications that help psychiatric conditions in children with otherwise normal development don’t seem to work as well for children who have autism spectrum disorders (ASDs), Dr. Jean A. Frazier said at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

"The effects seem to be maximized at lower doses than in typically developing youth, and the medications are often much less well tolerated," said Dr. Frazier, a professor of psychiatry at the University of Massachusetts, Worcester.

"If you do try them, the old axiom, ‘Start low, go slow,’ certainly applies."

Because there’s nothing that reliably ameliorates the core symptoms, clinicians and parents focus on treating the behavioral symptoms. Aggression, irritability, and self-injury; hyperactivity and anxiety; and sleep problems not only disrupt family life, but they also can endanger the child. A major cause of death among children with ASDs is "bolting" and falling into a neighbor’s swimming pool, or being hit by a car, Dr. Frazier said.

Michele G. Sullivan/Frontline Medical News

Risperidone and aripiprazole are approved by the Food and Drug Administration for the treatment of aggression and irritability. But the other commonly used medications, including selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics, and stimulants are used off label and supported by limited evidence, much of which is based on adult studies.

Risperidone is "pretty effective for reducing tantrums and self-injury," with stable gains over time, Dr. Frazier said. However, it’s associated with "huge weight gain." In its two pivotal trials, children taking risperidone gained an average of 5.6 kg over 6 months – about twice as much as investigators anticipated. This must be balanced with the fact that relapse will occur if treatment stops.

Aripiprazole also was effective in its two pivotal studies, but those were of short duration, she said. Both of the drugs are supported by A-level evidence – the highest grade.

Methylphenidate is used off label and is supported by B-level evidence. In two randomized, placebo-controlled studies, it was superior to placebo, but again, the studies were short and had small numbers enrolled. One of them reported very high levels of "intolerable side effects," including agitation, mood changes, and movement disorders. Divalproex sodium, lamotrigine, and naltrexone have much less supporting evidence.

SSRIs are used off label for repetitive behaviors. All of the evidence behind their use is based on adult studies, Dr. Frazier said. Case series of fluoxetine, quetiapine, and citalopram in children show "promise," but that promise hasn’t been confirmed in large randomized trials. In a recent pediatric citalopram study, many children showed increased energy, hyperactivity, decreased concentration, stereotypic behaviors, gastrointestinal issues, and dry skin.

A Cochrane review published last August found no evidence that SSRIs are of clinical benefit for children with ASDs and, it said "there is emerging evidence of harm" (Cochrane Database Syst. Rev. 2013;8).

The lack of SSRI effectiveness in children with autism spectrum disorders could be related to developmental differences in the serotonin uptake receptors, compared with normally developing children, Dr. Frazier added.

There are also few pediatric studies looking at medical therapy for sleep disorders in ASD. Melatonin is of interest in this arena. "Several recent randomized controlled trials of melatonin have been encouraging. They used up to 6 mg/night. It’s relatively benign, with almost no side effects."

Research continues, Dr. Frazier said. Gamma-aminobutyric acid and glutamate are being pursued as targets. Bumetanide is a loop diuretic used to treat heart failure – it also potentiates the action of gamma-aminobutyric acid. A recent study included 60 children with autism or Asperger’s disorder (Transl. Psychiatry 2012;2:e202). It showed significant improvements in the Childhood Autism Rating Scale and Clinical Global Impression score, but no changes relative to placebo on the Autism Diagnostic Observation Schedule.

Tetrahydrobiopterin is an essential co-factor for several metabolic pathways involved in the production of neurotransmitters. The most recent study randomized 46 children to tetrahydrobiopterin or placebo for 16 weeks (J. Child Adolesc. Psychopharmacol. 2013;23:320-8). There were no improvements on the CGI scales – the primary endpoints – but significant improvements were found in measures of language, social responsiveness, and aberrant and adaptive behavior.

"However, I caution you about taking these studies too much to heart, because they need to be replicated in larger groups," Dr. Frazier said.

Dr. Frazier reported receiving grant funding from GlaxoSmithKline, Hoffmann-La Roche, Neuren Pharmaceuticals, Pfizer, and Seaside Therapeutics.

[email protected]

NEW YORK – Neither approved nor investigational drugs seem to have much of an effect on the core symptoms of autism.

Medications that help psychiatric conditions in children with otherwise normal development don’t seem to work as well for children who have autism spectrum disorders (ASDs), Dr. Jean A. Frazier said at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

"The effects seem to be maximized at lower doses than in typically developing youth, and the medications are often much less well tolerated," said Dr. Frazier, a professor of psychiatry at the University of Massachusetts, Worcester.

"If you do try them, the old axiom, ‘Start low, go slow,’ certainly applies."

Because there’s nothing that reliably ameliorates the core symptoms, clinicians and parents focus on treating the behavioral symptoms. Aggression, irritability, and self-injury; hyperactivity and anxiety; and sleep problems not only disrupt family life, but they also can endanger the child. A major cause of death among children with ASDs is "bolting" and falling into a neighbor’s swimming pool, or being hit by a car, Dr. Frazier said.

Michele G. Sullivan/Frontline Medical News

Risperidone and aripiprazole are approved by the Food and Drug Administration for the treatment of aggression and irritability. But the other commonly used medications, including selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics, and stimulants are used off label and supported by limited evidence, much of which is based on adult studies.

Risperidone is "pretty effective for reducing tantrums and self-injury," with stable gains over time, Dr. Frazier said. However, it’s associated with "huge weight gain." In its two pivotal trials, children taking risperidone gained an average of 5.6 kg over 6 months – about twice as much as investigators anticipated. This must be balanced with the fact that relapse will occur if treatment stops.

Aripiprazole also was effective in its two pivotal studies, but those were of short duration, she said. Both of the drugs are supported by A-level evidence – the highest grade.

Methylphenidate is used off label and is supported by B-level evidence. In two randomized, placebo-controlled studies, it was superior to placebo, but again, the studies were short and had small numbers enrolled. One of them reported very high levels of "intolerable side effects," including agitation, mood changes, and movement disorders. Divalproex sodium, lamotrigine, and naltrexone have much less supporting evidence.

SSRIs are used off label for repetitive behaviors. All of the evidence behind their use is based on adult studies, Dr. Frazier said. Case series of fluoxetine, quetiapine, and citalopram in children show "promise," but that promise hasn’t been confirmed in large randomized trials. In a recent pediatric citalopram study, many children showed increased energy, hyperactivity, decreased concentration, stereotypic behaviors, gastrointestinal issues, and dry skin.

A Cochrane review published last August found no evidence that SSRIs are of clinical benefit for children with ASDs and, it said "there is emerging evidence of harm" (Cochrane Database Syst. Rev. 2013;8).

The lack of SSRI effectiveness in children with autism spectrum disorders could be related to developmental differences in the serotonin uptake receptors, compared with normally developing children, Dr. Frazier added.

There are also few pediatric studies looking at medical therapy for sleep disorders in ASD. Melatonin is of interest in this arena. "Several recent randomized controlled trials of melatonin have been encouraging. They used up to 6 mg/night. It’s relatively benign, with almost no side effects."

Research continues, Dr. Frazier said. Gamma-aminobutyric acid and glutamate are being pursued as targets. Bumetanide is a loop diuretic used to treat heart failure – it also potentiates the action of gamma-aminobutyric acid. A recent study included 60 children with autism or Asperger’s disorder (Transl. Psychiatry 2012;2:e202). It showed significant improvements in the Childhood Autism Rating Scale and Clinical Global Impression score, but no changes relative to placebo on the Autism Diagnostic Observation Schedule.

Tetrahydrobiopterin is an essential co-factor for several metabolic pathways involved in the production of neurotransmitters. The most recent study randomized 46 children to tetrahydrobiopterin or placebo for 16 weeks (J. Child Adolesc. Psychopharmacol. 2013;23:320-8). There were no improvements on the CGI scales – the primary endpoints – but significant improvements were found in measures of language, social responsiveness, and aberrant and adaptive behavior.

"However, I caution you about taking these studies too much to heart, because they need to be replicated in larger groups," Dr. Frazier said.

Dr. Frazier reported receiving grant funding from GlaxoSmithKline, Hoffmann-La Roche, Neuren Pharmaceuticals, Pfizer, and Seaside Therapeutics.

[email protected]

NEW YORK – Neither approved nor investigational drugs seem to have much of an effect on the core symptoms of autism.

Medications that help psychiatric conditions in children with otherwise normal development don’t seem to work as well for children who have autism spectrum disorders (ASDs), Dr. Jean A. Frazier said at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

"The effects seem to be maximized at lower doses than in typically developing youth, and the medications are often much less well tolerated," said Dr. Frazier, a professor of psychiatry at the University of Massachusetts, Worcester.

"If you do try them, the old axiom, ‘Start low, go slow,’ certainly applies."

Because there’s nothing that reliably ameliorates the core symptoms, clinicians and parents focus on treating the behavioral symptoms. Aggression, irritability, and self-injury; hyperactivity and anxiety; and sleep problems not only disrupt family life, but they also can endanger the child. A major cause of death among children with ASDs is "bolting" and falling into a neighbor’s swimming pool, or being hit by a car, Dr. Frazier said.

Michele G. Sullivan/Frontline Medical News

Risperidone and aripiprazole are approved by the Food and Drug Administration for the treatment of aggression and irritability. But the other commonly used medications, including selective serotonin reuptake inhibitors (SSRIs), atypical antipsychotics, and stimulants are used off label and supported by limited evidence, much of which is based on adult studies.

Risperidone is "pretty effective for reducing tantrums and self-injury," with stable gains over time, Dr. Frazier said. However, it’s associated with "huge weight gain." In its two pivotal trials, children taking risperidone gained an average of 5.6 kg over 6 months – about twice as much as investigators anticipated. This must be balanced with the fact that relapse will occur if treatment stops.

Aripiprazole also was effective in its two pivotal studies, but those were of short duration, she said. Both of the drugs are supported by A-level evidence – the highest grade.

Methylphenidate is used off label and is supported by B-level evidence. In two randomized, placebo-controlled studies, it was superior to placebo, but again, the studies were short and had small numbers enrolled. One of them reported very high levels of "intolerable side effects," including agitation, mood changes, and movement disorders. Divalproex sodium, lamotrigine, and naltrexone have much less supporting evidence.

SSRIs are used off label for repetitive behaviors. All of the evidence behind their use is based on adult studies, Dr. Frazier said. Case series of fluoxetine, quetiapine, and citalopram in children show "promise," but that promise hasn’t been confirmed in large randomized trials. In a recent pediatric citalopram study, many children showed increased energy, hyperactivity, decreased concentration, stereotypic behaviors, gastrointestinal issues, and dry skin.

A Cochrane review published last August found no evidence that SSRIs are of clinical benefit for children with ASDs and, it said "there is emerging evidence of harm" (Cochrane Database Syst. Rev. 2013;8).

The lack of SSRI effectiveness in children with autism spectrum disorders could be related to developmental differences in the serotonin uptake receptors, compared with normally developing children, Dr. Frazier added.

There are also few pediatric studies looking at medical therapy for sleep disorders in ASD. Melatonin is of interest in this arena. "Several recent randomized controlled trials of melatonin have been encouraging. They used up to 6 mg/night. It’s relatively benign, with almost no side effects."

Research continues, Dr. Frazier said. Gamma-aminobutyric acid and glutamate are being pursued as targets. Bumetanide is a loop diuretic used to treat heart failure – it also potentiates the action of gamma-aminobutyric acid. A recent study included 60 children with autism or Asperger’s disorder (Transl. Psychiatry 2012;2:e202). It showed significant improvements in the Childhood Autism Rating Scale and Clinical Global Impression score, but no changes relative to placebo on the Autism Diagnostic Observation Schedule.

Tetrahydrobiopterin is an essential co-factor for several metabolic pathways involved in the production of neurotransmitters. The most recent study randomized 46 children to tetrahydrobiopterin or placebo for 16 weeks (J. Child Adolesc. Psychopharmacol. 2013;23:320-8). There were no improvements on the CGI scales – the primary endpoints – but significant improvements were found in measures of language, social responsiveness, and aberrant and adaptive behavior.

"However, I caution you about taking these studies too much to heart, because they need to be replicated in larger groups," Dr. Frazier said.

Dr. Frazier reported receiving grant funding from GlaxoSmithKline, Hoffmann-La Roche, Neuren Pharmaceuticals, Pfizer, and Seaside Therapeutics.

[email protected]