Dan Hurley

NEW YORK — Aggressive treatment of child and adolescent anxiety disorders is the key to clinical success, according to Dr. John T. Walkup.

“The biggest mistake you can make is to half treat,” Dr. Walkup, vice chair of psychiatry and director of the division of child and adolescent psychiatry at Cornell University, New York, said at a pharmacology update sponsored by the American Association of Child and Adolescent Psychiatry.

The biggest issue in consultation is underdosing. “As long as they're safe, I'm monitoring carefully, and they haven't had full recovery, I increase [the] dose,” he said.

Cognitive-behavioral therapy (CBT) for obsessive-compulsive disorder (OCD) also must be done energetically, Dr. Walkup said.

He cited the proactive approach taken largely by investigators at the University of Pennsylvania, Philadelphia, in the Pediatric OCD Treatment Study (POTS). That multisite, placebo-controlled, double-blind trial compared sertraline alone, CBT alone, and combination therapy for the treatment of OCD. The investigators found that CBT alone and sertraline alone did not bring results that were significantly different (JAMA 2004;292:1969–76).

The University of Pennsylvania providers “are not quiet, easygoing therapists. These are tough, fast, energizing, engaging,” he said. “But if you're going to be an effective OCD therapist, you have to be.”

Whatever the treatment modality, the first step is proper diagnosis. Mistaking the disorder for variants of attention-deficit/hyperactivity disorder (ADHD) or bipolar disorder can lead to lost months and poor outcomes, Dr. Walkup said.

“Both ADHD and anxiety tend to develop around the same age, ages 6–10. But the anxious kids tend to be inattentive because they're worried about their mom; they're worried about the nurse; their mind is just cluttered with worry; and the last thing they can do is pay attention,” he said.

A similar case of mistaken diagnosis is sometimes made with bipolar disorder. Dr. Walkup drew applause from the audience when he said: “If you see something affective in a kid before 12, think anxiety, don't think bipolar. The rate of anxiety to bipolar is 20 or 40 to 1.”

The stakes are high, he emphasized, when it comes to making an accurate diagnosis and offering adequate treatment for anxiety disorders. “The morbidity is high: suicide, depression, performance,” Dr. Walkup said.

Asked by an audience member how quickly he raises an initial dose of sertraline, he said: “When you start a drug trial, get going. You offer hope and encouragement, and a brisk response that make kids and families responsive to treatment. I start at 25 mg the first week, 50 the second week, and hold at 50.

“If the symptoms are nonresponsive, at week 4, I go to 100. If still nonresponsive, after another 2 weeks, I go to 150, and up to 200 if necessary by week 8.”

When the highest safe dose is ineffective, he considers switching to a second selective serotonin reuptake inhibitor or lithium, Dr. Walkup said. His protocol is a slow cross-taper, gradually adding the second drug and seeing a benefit before even considering a reduction of the first.

“You're usually recommended to discontinue the first medication before you start the new,” he said. “The problem is that even the nonresponders probably had some benefit on that first drug. When you begin to discontinue, those symptoms that got better begin to creep back.”

Instead, he prefers what he calls “getting stuck in the middle.”

“You've got them on one drug; you add another,” Dr. Walkup said. “You want an enhancement on the second medication before you begin to discontinue the first. Within a brief period, you see what seems to be a lithium augmentation…. I stop, I hold, and I do not discontinue. I get stuck in the middle of a cross-taper.

“The process is not 2 or 3 weeks. It's much longer. How long? Families are impatient. Insurers are impatient. You've got to educate, educate, educate.”

Once significant relief of anxiety is achieved, he prefers to wait a year before attempting to reduce or eliminate medication. “Those who deteriorate during discontinuation usually do so within 6 weeks. If I can get them through that 6-week period, I know I have a pretty good chance of taking them down another notch,” he said.

Disclosures: Dr. Walkup has served on the advisory board of the Tourette Syndrome Association (TSA); received grant support from the TSA; and received honorarium and travel support from AACAP, and additional support from Abbott Laboratories, the Centers for Disease Control and Prevention, Eli Lilly & Co., and Pfizer Inc.

NEW YORK — Aggressive treatment of child and adolescent anxiety disorders is the key to clinical success, according to Dr. John T. Walkup.

“The biggest mistake you can make is to half treat,” Dr. Walkup, vice chair of psychiatry and director of the division of child and adolescent psychiatry at Cornell University, New York, said at a pharmacology update sponsored by the American Association of Child and Adolescent Psychiatry.

The biggest issue in consultation is underdosing. “As long as they're safe, I'm monitoring carefully, and they haven't had full recovery, I increase [the] dose,” he said.

Cognitive-behavioral therapy (CBT) for obsessive-compulsive disorder (OCD) also must be done energetically, Dr. Walkup said.

He cited the proactive approach taken largely by investigators at the University of Pennsylvania, Philadelphia, in the Pediatric OCD Treatment Study (POTS). That multisite, placebo-controlled, double-blind trial compared sertraline alone, CBT alone, and combination therapy for the treatment of OCD. The investigators found that CBT alone and sertraline alone did not bring results that were significantly different (JAMA 2004;292:1969–76).

The University of Pennsylvania providers “are not quiet, easygoing therapists. These are tough, fast, energizing, engaging,” he said. “But if you're going to be an effective OCD therapist, you have to be.”

Whatever the treatment modality, the first step is proper diagnosis. Mistaking the disorder for variants of attention-deficit/hyperactivity disorder (ADHD) or bipolar disorder can lead to lost months and poor outcomes, Dr. Walkup said.

“Both ADHD and anxiety tend to develop around the same age, ages 6–10. But the anxious kids tend to be inattentive because they're worried about their mom; they're worried about the nurse; their mind is just cluttered with worry; and the last thing they can do is pay attention,” he said.

A similar case of mistaken diagnosis is sometimes made with bipolar disorder. Dr. Walkup drew applause from the audience when he said: “If you see something affective in a kid before 12, think anxiety, don't think bipolar. The rate of anxiety to bipolar is 20 or 40 to 1.”

The stakes are high, he emphasized, when it comes to making an accurate diagnosis and offering adequate treatment for anxiety disorders. “The morbidity is high: suicide, depression, performance,” Dr. Walkup said.

Asked by an audience member how quickly he raises an initial dose of sertraline, he said: “When you start a drug trial, get going. You offer hope and encouragement, and a brisk response that make kids and families responsive to treatment. I start at 25 mg the first week, 50 the second week, and hold at 50.

“If the symptoms are nonresponsive, at week 4, I go to 100. If still nonresponsive, after another 2 weeks, I go to 150, and up to 200 if necessary by week 8.”

When the highest safe dose is ineffective, he considers switching to a second selective serotonin reuptake inhibitor or lithium, Dr. Walkup said. His protocol is a slow cross-taper, gradually adding the second drug and seeing a benefit before even considering a reduction of the first.

“You're usually recommended to discontinue the first medication before you start the new,” he said. “The problem is that even the nonresponders probably had some benefit on that first drug. When you begin to discontinue, those symptoms that got better begin to creep back.”

Instead, he prefers what he calls “getting stuck in the middle.”

“You've got them on one drug; you add another,” Dr. Walkup said. “You want an enhancement on the second medication before you begin to discontinue the first. Within a brief period, you see what seems to be a lithium augmentation…. I stop, I hold, and I do not discontinue. I get stuck in the middle of a cross-taper.

“The process is not 2 or 3 weeks. It's much longer. How long? Families are impatient. Insurers are impatient. You've got to educate, educate, educate.”

Once significant relief of anxiety is achieved, he prefers to wait a year before attempting to reduce or eliminate medication. “Those who deteriorate during discontinuation usually do so within 6 weeks. If I can get them through that 6-week period, I know I have a pretty good chance of taking them down another notch,” he said.

Disclosures: Dr. Walkup has served on the advisory board of the Tourette Syndrome Association (TSA); received grant support from the TSA; and received honorarium and travel support from AACAP, and additional support from Abbott Laboratories, the Centers for Disease Control and Prevention, Eli Lilly & Co., and Pfizer Inc.

NEW YORK — Aggressive treatment of child and adolescent anxiety disorders is the key to clinical success, according to Dr. John T. Walkup.

“The biggest mistake you can make is to half treat,” Dr. Walkup, vice chair of psychiatry and director of the division of child and adolescent psychiatry at Cornell University, New York, said at a pharmacology update sponsored by the American Association of Child and Adolescent Psychiatry.

The biggest issue in consultation is underdosing. “As long as they're safe, I'm monitoring carefully, and they haven't had full recovery, I increase [the] dose,” he said.

Cognitive-behavioral therapy (CBT) for obsessive-compulsive disorder (OCD) also must be done energetically, Dr. Walkup said.

He cited the proactive approach taken largely by investigators at the University of Pennsylvania, Philadelphia, in the Pediatric OCD Treatment Study (POTS). That multisite, placebo-controlled, double-blind trial compared sertraline alone, CBT alone, and combination therapy for the treatment of OCD. The investigators found that CBT alone and sertraline alone did not bring results that were significantly different (JAMA 2004;292:1969–76).

The University of Pennsylvania providers “are not quiet, easygoing therapists. These are tough, fast, energizing, engaging,” he said. “But if you're going to be an effective OCD therapist, you have to be.”

Whatever the treatment modality, the first step is proper diagnosis. Mistaking the disorder for variants of attention-deficit/hyperactivity disorder (ADHD) or bipolar disorder can lead to lost months and poor outcomes, Dr. Walkup said.

“Both ADHD and anxiety tend to develop around the same age, ages 6–10. But the anxious kids tend to be inattentive because they're worried about their mom; they're worried about the nurse; their mind is just cluttered with worry; and the last thing they can do is pay attention,” he said.

A similar case of mistaken diagnosis is sometimes made with bipolar disorder. Dr. Walkup drew applause from the audience when he said: “If you see something affective in a kid before 12, think anxiety, don't think bipolar. The rate of anxiety to bipolar is 20 or 40 to 1.”

The stakes are high, he emphasized, when it comes to making an accurate diagnosis and offering adequate treatment for anxiety disorders. “The morbidity is high: suicide, depression, performance,” Dr. Walkup said.

Asked by an audience member how quickly he raises an initial dose of sertraline, he said: “When you start a drug trial, get going. You offer hope and encouragement, and a brisk response that make kids and families responsive to treatment. I start at 25 mg the first week, 50 the second week, and hold at 50.

“If the symptoms are nonresponsive, at week 4, I go to 100. If still nonresponsive, after another 2 weeks, I go to 150, and up to 200 if necessary by week 8.”

When the highest safe dose is ineffective, he considers switching to a second selective serotonin reuptake inhibitor or lithium, Dr. Walkup said. His protocol is a slow cross-taper, gradually adding the second drug and seeing a benefit before even considering a reduction of the first.

“You're usually recommended to discontinue the first medication before you start the new,” he said. “The problem is that even the nonresponders probably had some benefit on that first drug. When you begin to discontinue, those symptoms that got better begin to creep back.”

Instead, he prefers what he calls “getting stuck in the middle.”

“You've got them on one drug; you add another,” Dr. Walkup said. “You want an enhancement on the second medication before you begin to discontinue the first. Within a brief period, you see what seems to be a lithium augmentation…. I stop, I hold, and I do not discontinue. I get stuck in the middle of a cross-taper.

“The process is not 2 or 3 weeks. It's much longer. How long? Families are impatient. Insurers are impatient. You've got to educate, educate, educate.”

Once significant relief of anxiety is achieved, he prefers to wait a year before attempting to reduce or eliminate medication. “Those who deteriorate during discontinuation usually do so within 6 weeks. If I can get them through that 6-week period, I know I have a pretty good chance of taking them down another notch,” he said.

Disclosures: Dr. Walkup has served on the advisory board of the Tourette Syndrome Association (TSA); received grant support from the TSA; and received honorarium and travel support from AACAP, and additional support from Abbott Laboratories, the Centers for Disease Control and Prevention, Eli Lilly & Co., and Pfizer Inc.

NEW YORK — A wealth of new data is emerging that will help clinicians anticipate and manage endocrine complications of psychotropic drugs, according to a leading researcher.

“We can't take a gene chip and come up with firm recommendations,” said Dr. Harold E. Carlson, who has published widely in the field as professor of medicine and endocrinology at Stony Brook (New York) University Health Sciences Center. But based on new data, he said, “We can think about individualized pharmacotherapy tailored to your patients' needs.'

Reduced height and weight in children and adolescents taking stimulants for attention-deficit/hyperactivity disorder (ADHD) has been a concern for years, and the latest data from the Multimodal Treatment of ADHD (MTA) Study suggest that growth deficits of about 1 inch persist after 8 years of treatment (J. Am. Acad. Child Adolesc. Psychiatry 2009; 48:484-500.)

“We still do not have published data on the final adult height of children who have been treated continuously from childhood with stimulants,” Dr. Carlson said at a psychopharmacology update, sponsored by the American Academy of Child and Adolescent Psychiatry (AACAP). “The MTA study is nearing the point where most of the subjects will reach their final adult type. So far, [co–principal investigator] Jim Swanson tells me they remain about 1 inch shorter than they should otherwise be. They may wind up with a permanent growth deficit.”

On the other hand, permanent growth deficits were not observed in a study of atomoxetine (J. Child Adolesc. Psychopharmacol. 2007;17:689-700). In the study of 61 children treated for 5 years, initial slowing of growth was followed by a period of catch-up, such that height was usually normal by the fourth or fifth year.

Individual characteristics of patients can alert clinicians to those who might be at increased risk of reduced growth, Dr. Carlson noted. Prepubertal children have more slowing of growth than do adolescents; boys have more slowing than do girls; and children who are tall or overweight at the inception of treatment are at greater risk of slowed growth than shorter, underweight children.

The bottom line, Dr. Carlson said, is that all children and adolescents need to have their height and weight measured before beginning stimulant treatment.

“Get the growth charts. And then someone should measure height and weight every 6 to 12 months. If the kid seems to be falling off his or her growth curve, and it's a substantial amount, then I think it's time to … consider referring to a pediatric endocrinologist.”

Dr. Carlson urged physicians to use the lowest effective dose, to avoid giving short-acting stimulants just before meals, and to provide high-energy snacks or meals when the appetite is least suppressed.

The opposite metabolic effect—weight gain associated with antipsychotics—has been confirmed in multiple studies cited by Dr. Carlson, including one study (J. Am. Acad. Child Adolesc. Psychiatry 2002;413:337-43) showing that olanzapine and risperidone are both associated with “extreme” weight gain in adolescents. The best defense against such unwanted effects, he said, is a good offense.

“You're going to want to calculate the child's BMI before you begin treatment, and then monitor it at every visit,” he said. “Provide counseling on diet and exercise from the start. It's much harder to take it off than to prevent it. Structured programs work best. If weight is progressing quickly, try switching medications to one less associated with weight gain. In resistant cases, pharmaceutical therapies have been used to promote weight loss, such as orlistat or metformin.”

Sudden cardiac death is another risk to consider when prescribing stimulant medications for ADHD, Dr. Carlson noted.

Confusion has ensued from the varying recommendations for and against routine ECGs by the American Heart Association, the American Academy of Pediatrics, and the AACAP, however, “All three groups agree you need a good cardiac history, a detailed family history, and a careful physical exam,” Dr. Carlson said. “All agree an ECG should be performed if the initial valuation suggested increased cardiac risk, but the ECG does not need to be done in the absence of such findings.”

Despite the growing consensus, he added, “We're not at the end of the story yet.” The fact is, Dr. Carlson pointed out, no firm data have yet established whether or not ADHD medications truly do increase the risk of sudden cardiac death, and if so, by how much.

However, in what Dr. Carlson described as “the earthquake of several months ago,” a case-control study found that youths who died of sudden cardiac death were 7.4 times more likely to be taking stimulants for ADHD than were youths who died as passengers in automobile accents (Am. J. Psychiatry 2009;166:992-1001).

“The study had a bunch of flaws, pointed out in editorial and letters since,” Dr. Carlson noted. “The FDA has not changed its policy as a result.”

With a large study now underway aimed at replicating the data in that 2009 study, Dr. Carlson said, “I would surely hope that with an n of 100,000, we should get a good answer. So stay tuned.”

Dr. Carlson disclosed financial relationships with several pharmaceutical companies, including Eli Lilly & Co.; Janssen L.P.; Ortho-McNeil-Janssen Pharmaceuticals Inc.; Otsuka America Pharmaceutical Inc.; Bristol-Myers Squibb Co.; Cephalon Inc.; McNeil Pediatrics, a division of McNeil-PPC Inc.; and Shire U.S. Inc.

NEW YORK — A wealth of new data is emerging that will help clinicians anticipate and manage endocrine complications of psychotropic drugs, according to a leading researcher.

“We can't take a gene chip and come up with firm recommendations,” said Dr. Harold E. Carlson, who has published widely in the field as professor of medicine and endocrinology at Stony Brook (New York) University Health Sciences Center. But based on new data, he said, “We can think about individualized pharmacotherapy tailored to your patients' needs.'

Reduced height and weight in children and adolescents taking stimulants for attention-deficit/hyperactivity disorder (ADHD) has been a concern for years, and the latest data from the Multimodal Treatment of ADHD (MTA) Study suggest that growth deficits of about 1 inch persist after 8 years of treatment (J. Am. Acad. Child Adolesc. Psychiatry 2009; 48:484-500.)

“We still do not have published data on the final adult height of children who have been treated continuously from childhood with stimulants,” Dr. Carlson said at a psychopharmacology update, sponsored by the American Academy of Child and Adolescent Psychiatry (AACAP). “The MTA study is nearing the point where most of the subjects will reach their final adult type. So far, [co–principal investigator] Jim Swanson tells me they remain about 1 inch shorter than they should otherwise be. They may wind up with a permanent growth deficit.”

On the other hand, permanent growth deficits were not observed in a study of atomoxetine (J. Child Adolesc. Psychopharmacol. 2007;17:689-700). In the study of 61 children treated for 5 years, initial slowing of growth was followed by a period of catch-up, such that height was usually normal by the fourth or fifth year.

Individual characteristics of patients can alert clinicians to those who might be at increased risk of reduced growth, Dr. Carlson noted. Prepubertal children have more slowing of growth than do adolescents; boys have more slowing than do girls; and children who are tall or overweight at the inception of treatment are at greater risk of slowed growth than shorter, underweight children.

The bottom line, Dr. Carlson said, is that all children and adolescents need to have their height and weight measured before beginning stimulant treatment.

“Get the growth charts. And then someone should measure height and weight every 6 to 12 months. If the kid seems to be falling off his or her growth curve, and it's a substantial amount, then I think it's time to … consider referring to a pediatric endocrinologist.”

Dr. Carlson urged physicians to use the lowest effective dose, to avoid giving short-acting stimulants just before meals, and to provide high-energy snacks or meals when the appetite is least suppressed.

The opposite metabolic effect—weight gain associated with antipsychotics—has been confirmed in multiple studies cited by Dr. Carlson, including one study (J. Am. Acad. Child Adolesc. Psychiatry 2002;413:337-43) showing that olanzapine and risperidone are both associated with “extreme” weight gain in adolescents. The best defense against such unwanted effects, he said, is a good offense.

“You're going to want to calculate the child's BMI before you begin treatment, and then monitor it at every visit,” he said. “Provide counseling on diet and exercise from the start. It's much harder to take it off than to prevent it. Structured programs work best. If weight is progressing quickly, try switching medications to one less associated with weight gain. In resistant cases, pharmaceutical therapies have been used to promote weight loss, such as orlistat or metformin.”

Sudden cardiac death is another risk to consider when prescribing stimulant medications for ADHD, Dr. Carlson noted.

Confusion has ensued from the varying recommendations for and against routine ECGs by the American Heart Association, the American Academy of Pediatrics, and the AACAP, however, “All three groups agree you need a good cardiac history, a detailed family history, and a careful physical exam,” Dr. Carlson said. “All agree an ECG should be performed if the initial valuation suggested increased cardiac risk, but the ECG does not need to be done in the absence of such findings.”

Despite the growing consensus, he added, “We're not at the end of the story yet.” The fact is, Dr. Carlson pointed out, no firm data have yet established whether or not ADHD medications truly do increase the risk of sudden cardiac death, and if so, by how much.

However, in what Dr. Carlson described as “the earthquake of several months ago,” a case-control study found that youths who died of sudden cardiac death were 7.4 times more likely to be taking stimulants for ADHD than were youths who died as passengers in automobile accents (Am. J. Psychiatry 2009;166:992-1001).

“The study had a bunch of flaws, pointed out in editorial and letters since,” Dr. Carlson noted. “The FDA has not changed its policy as a result.”

With a large study now underway aimed at replicating the data in that 2009 study, Dr. Carlson said, “I would surely hope that with an n of 100,000, we should get a good answer. So stay tuned.”

Dr. Carlson disclosed financial relationships with several pharmaceutical companies, including Eli Lilly & Co.; Janssen L.P.; Ortho-McNeil-Janssen Pharmaceuticals Inc.; Otsuka America Pharmaceutical Inc.; Bristol-Myers Squibb Co.; Cephalon Inc.; McNeil Pediatrics, a division of McNeil-PPC Inc.; and Shire U.S. Inc.

NEW YORK — A wealth of new data is emerging that will help clinicians anticipate and manage endocrine complications of psychotropic drugs, according to a leading researcher.

“We can't take a gene chip and come up with firm recommendations,” said Dr. Harold E. Carlson, who has published widely in the field as professor of medicine and endocrinology at Stony Brook (New York) University Health Sciences Center. But based on new data, he said, “We can think about individualized pharmacotherapy tailored to your patients' needs.'

Reduced height and weight in children and adolescents taking stimulants for attention-deficit/hyperactivity disorder (ADHD) has been a concern for years, and the latest data from the Multimodal Treatment of ADHD (MTA) Study suggest that growth deficits of about 1 inch persist after 8 years of treatment (J. Am. Acad. Child Adolesc. Psychiatry 2009; 48:484-500.)

“We still do not have published data on the final adult height of children who have been treated continuously from childhood with stimulants,” Dr. Carlson said at a psychopharmacology update, sponsored by the American Academy of Child and Adolescent Psychiatry (AACAP). “The MTA study is nearing the point where most of the subjects will reach their final adult type. So far, [co–principal investigator] Jim Swanson tells me they remain about 1 inch shorter than they should otherwise be. They may wind up with a permanent growth deficit.”

On the other hand, permanent growth deficits were not observed in a study of atomoxetine (J. Child Adolesc. Psychopharmacol. 2007;17:689-700). In the study of 61 children treated for 5 years, initial slowing of growth was followed by a period of catch-up, such that height was usually normal by the fourth or fifth year.

Individual characteristics of patients can alert clinicians to those who might be at increased risk of reduced growth, Dr. Carlson noted. Prepubertal children have more slowing of growth than do adolescents; boys have more slowing than do girls; and children who are tall or overweight at the inception of treatment are at greater risk of slowed growth than shorter, underweight children.

The bottom line, Dr. Carlson said, is that all children and adolescents need to have their height and weight measured before beginning stimulant treatment.

“Get the growth charts. And then someone should measure height and weight every 6 to 12 months. If the kid seems to be falling off his or her growth curve, and it's a substantial amount, then I think it's time to … consider referring to a pediatric endocrinologist.”

Dr. Carlson urged physicians to use the lowest effective dose, to avoid giving short-acting stimulants just before meals, and to provide high-energy snacks or meals when the appetite is least suppressed.

The opposite metabolic effect—weight gain associated with antipsychotics—has been confirmed in multiple studies cited by Dr. Carlson, including one study (J. Am. Acad. Child Adolesc. Psychiatry 2002;413:337-43) showing that olanzapine and risperidone are both associated with “extreme” weight gain in adolescents. The best defense against such unwanted effects, he said, is a good offense.

“You're going to want to calculate the child's BMI before you begin treatment, and then monitor it at every visit,” he said. “Provide counseling on diet and exercise from the start. It's much harder to take it off than to prevent it. Structured programs work best. If weight is progressing quickly, try switching medications to one less associated with weight gain. In resistant cases, pharmaceutical therapies have been used to promote weight loss, such as orlistat or metformin.”

Sudden cardiac death is another risk to consider when prescribing stimulant medications for ADHD, Dr. Carlson noted.

Confusion has ensued from the varying recommendations for and against routine ECGs by the American Heart Association, the American Academy of Pediatrics, and the AACAP, however, “All three groups agree you need a good cardiac history, a detailed family history, and a careful physical exam,” Dr. Carlson said. “All agree an ECG should be performed if the initial valuation suggested increased cardiac risk, but the ECG does not need to be done in the absence of such findings.”

Despite the growing consensus, he added, “We're not at the end of the story yet.” The fact is, Dr. Carlson pointed out, no firm data have yet established whether or not ADHD medications truly do increase the risk of sudden cardiac death, and if so, by how much.

However, in what Dr. Carlson described as “the earthquake of several months ago,” a case-control study found that youths who died of sudden cardiac death were 7.4 times more likely to be taking stimulants for ADHD than were youths who died as passengers in automobile accents (Am. J. Psychiatry 2009;166:992-1001).

“The study had a bunch of flaws, pointed out in editorial and letters since,” Dr. Carlson noted. “The FDA has not changed its policy as a result.”

With a large study now underway aimed at replicating the data in that 2009 study, Dr. Carlson said, “I would surely hope that with an n of 100,000, we should get a good answer. So stay tuned.”

Dr. Carlson disclosed financial relationships with several pharmaceutical companies, including Eli Lilly & Co.; Janssen L.P.; Ortho-McNeil-Janssen Pharmaceuticals Inc.; Otsuka America Pharmaceutical Inc.; Bristol-Myers Squibb Co.; Cephalon Inc.; McNeil Pediatrics, a division of McNeil-PPC Inc.; and Shire U.S. Inc.

NEW YORK – Sticking with medications that have shown positive results in randomized trials is important when it comes to treating pediatric depression, according to Dr. Karen Dineen Wagner.

The Food Drug Administration has approved only two drugs for treatment of pediatric depression–fluoxetine for patients aged 8 to 17 years, and escitalopram for those aged 12 to 17–but she pointed out that citalopram also showed positive results in a published trial, and that sertraline has shown positive results in ages 6 to 17 in an a priori pooled analysis of two studies (even though the individual trials were negative).

“Keep within those we know about,” Dr. Wagner advised at a pharmacology update, sponsored by the American Academy of Child and Adolescent Psychiatry (AACAP). She pointed out that budeprion, although widely prescribed, has not been shown effective in any published trial of a pediatric population. “Some parents want to know: Is this drug FDA approved [for use in children]? If you use medications that are not FDA-approved, you want to stay as best you can with those that have shown some efficacy [for use] in children, in the age group you're treating.”

Dr. Wagner said the only published trial of omega-3 fatty acids in prepubertal depression was small–involving 28 children–and while 70% of those in the treatment arm showed at least a 50% improvement, none of those on placebo did so (Am. J. Psychiatry 2006;163:1098-100).<

“Never in any study I've been involved in has there been a zero placebo response rate,” said Dr. Wagner, who is the Marie B. Gale Centennial Professor and vice chairwoman of the department of psychiatry and behavior sciences at the University of Texas Medical Branch in Galveston. “But who knows? It was published.”

Many of the trials that failed to show positive results, she said, did so not because the treatment arms showed low response rates, but because the placebo arms showed high improvement rates.

“What makes the placebo response rates so high in children?” Dr. Wagner asked. She cited a recent meta-analysis showing that the chief predictor of a high placebo response rate is the number of study sites (Am. J. Psychiatry 2009;166:42-9).

“Another predictor of a high placebo response rate is the baseline of severity. If a child is enrolled with moderate depression, it's very likely they'll respond to placebo as well as to medication.”

Although the Treatment for Adolescents With Depression Study (TADS) showed that cognitive-behavioral therapy (CBT) can be as effective as medication in improving symptoms at 36 weeks, Dr. Wagner noted that it was less effective at 12 weeks (Arch. Gen. Psychiatry 2007;64:1132-44; Am. J. Psychiatry 2009;166:337-44).<

“What [the study] shows is that CBT is effective, but it takes a while to work,” she said. “Parents have to be advised about that. Some will get better early, but for the most part it will take time. The medication will work faster. For moderate to severe depression, CBT just may take too long.”

She pointed to another analysis of TADS that found that the rate of attempted suicides or suicidal ideation between those on medication and those on placebo did not vary over the course of the study (J. Clin. Psychiatry 2009;70:741-7). “You would think if there was a drug effect, there would be a timing to it,” she said.

One of the key predictors of suicidal attempts or ideation in TADS was acute interpersonal conflict. “Usually, it was a fight or conflict with a parent,” Dr. Wagner said. “This needs to be discussed with parents. Keeping conflict low is important.”

In addressing the question of whether to switch to another selective serotonin reuptake inhibitor or to another class of drugs when an adolescent fails initial therapy, Dr. Wagner asked for a show of hands from the psychiatrists in attendance as to which strategy they would prefer.

“Everybody who raised their hand was correct,”she said, citing recent evidence from the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) trial (JAMA 2008;299:901-13). “If your child fails an SSRI, they have a 50% chance of doing well on another SSRI and a 50% chance of improvement on a different class. Adding CBT increases the chances of improvement by about 11%.”

Like TADS, the TORDIA trial also found that family conflict is a leading predictor of suicide attempts, as is baseline suicidal ideation.

“Ideation in the face of family conflict is a group to watch very carefully,” she emphasized.

Guidance on how long a clinician should wait before deciding whether an initial treatment needs to be changed or supplemented came from study that was published last year (J. Am. Acad. Child Adolesc. Psychiatry 2009;48:71-8).

According to that study, Dr. Wagner said, “If by week 4, they haven't had a 58% improvement–if they're not more than 50% improved–they're unlikely to go on to remit. It's time to up the dose or switch.”

A successful therapy should be maintained for at least a year before attempting to cease treatment, Dr. Wagner said (J. Child. Adolesc. Psychopharmacol. 2008;18:389-94). “A year from the time you start treatment would be a bare minimum. I know a lot of parents want it short, but then it's important that they understand and assume the risk,” she said.

As to the box warnings on suicide risk that were issued by the FDA in 2004 and 2007, she referred to findings that showed a 44% decrease in primary care providers' diagnoses of depression after the warnings were issued and a 10% reduction in prescriptions of SSRIs (Arch. Gen. Psychiatry 2009;66:633-9).

“Where did those children who were previously being diagnosed with depression go?” Dr. Wagner asked. “The suicide rate is now 5% higher than it has been in the previous 20 years. It's worrisome that diagnosis … and treatment has dropped. There's increasing evidence that those trends could be an unintended consequence of the FDA's box warning.”

She concluded by citing another study that showed that the number of children needed to treat with antidepressants to achieve one remission is 10, while the comparable number needed to harm due to suicidal ideation or attempts is 112 (JAMA 2007;297:1683-96).

“That's not committing suicide but having suicidal attempts or ideation,” she emphasized. “They are 11 times more likely to get benefit than to develop suicidality. From my perspective, that's an excellent ratio.”

Dr. Wagner disclosed that she has received honorarium and travel support from AACAP, research support from National Institute of Mental Health, and other support from the American Society of Clinical Pharmacology.

NEW YORK – Sticking with medications that have shown positive results in randomized trials is important when it comes to treating pediatric depression, according to Dr. Karen Dineen Wagner.

The Food Drug Administration has approved only two drugs for treatment of pediatric depression–fluoxetine for patients aged 8 to 17 years, and escitalopram for those aged 12 to 17–but she pointed out that citalopram also showed positive results in a published trial, and that sertraline has shown positive results in ages 6 to 17 in an a priori pooled analysis of two studies (even though the individual trials were negative).

“Keep within those we know about,” Dr. Wagner advised at a pharmacology update, sponsored by the American Academy of Child and Adolescent Psychiatry (AACAP). She pointed out that budeprion, although widely prescribed, has not been shown effective in any published trial of a pediatric population. “Some parents want to know: Is this drug FDA approved [for use in children]? If you use medications that are not FDA-approved, you want to stay as best you can with those that have shown some efficacy [for use] in children, in the age group you're treating.”

Dr. Wagner said the only published trial of omega-3 fatty acids in prepubertal depression was small–involving 28 children–and while 70% of those in the treatment arm showed at least a 50% improvement, none of those on placebo did so (Am. J. Psychiatry 2006;163:1098-100).<

“Never in any study I've been involved in has there been a zero placebo response rate,” said Dr. Wagner, who is the Marie B. Gale Centennial Professor and vice chairwoman of the department of psychiatry and behavior sciences at the University of Texas Medical Branch in Galveston. “But who knows? It was published.”

Many of the trials that failed to show positive results, she said, did so not because the treatment arms showed low response rates, but because the placebo arms showed high improvement rates.

“What makes the placebo response rates so high in children?” Dr. Wagner asked. She cited a recent meta-analysis showing that the chief predictor of a high placebo response rate is the number of study sites (Am. J. Psychiatry 2009;166:42-9).

“Another predictor of a high placebo response rate is the baseline of severity. If a child is enrolled with moderate depression, it's very likely they'll respond to placebo as well as to medication.”

Although the Treatment for Adolescents With Depression Study (TADS) showed that cognitive-behavioral therapy (CBT) can be as effective as medication in improving symptoms at 36 weeks, Dr. Wagner noted that it was less effective at 12 weeks (Arch. Gen. Psychiatry 2007;64:1132-44; Am. J. Psychiatry 2009;166:337-44).<

“What [the study] shows is that CBT is effective, but it takes a while to work,” she said. “Parents have to be advised about that. Some will get better early, but for the most part it will take time. The medication will work faster. For moderate to severe depression, CBT just may take too long.”

She pointed to another analysis of TADS that found that the rate of attempted suicides or suicidal ideation between those on medication and those on placebo did not vary over the course of the study (J. Clin. Psychiatry 2009;70:741-7). “You would think if there was a drug effect, there would be a timing to it,” she said.

One of the key predictors of suicidal attempts or ideation in TADS was acute interpersonal conflict. “Usually, it was a fight or conflict with a parent,” Dr. Wagner said. “This needs to be discussed with parents. Keeping conflict low is important.”

In addressing the question of whether to switch to another selective serotonin reuptake inhibitor or to another class of drugs when an adolescent fails initial therapy, Dr. Wagner asked for a show of hands from the psychiatrists in attendance as to which strategy they would prefer.

“Everybody who raised their hand was correct,”she said, citing recent evidence from the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) trial (JAMA 2008;299:901-13). “If your child fails an SSRI, they have a 50% chance of doing well on another SSRI and a 50% chance of improvement on a different class. Adding CBT increases the chances of improvement by about 11%.”

Like TADS, the TORDIA trial also found that family conflict is a leading predictor of suicide attempts, as is baseline suicidal ideation.

“Ideation in the face of family conflict is a group to watch very carefully,” she emphasized.

Guidance on how long a clinician should wait before deciding whether an initial treatment needs to be changed or supplemented came from study that was published last year (J. Am. Acad. Child Adolesc. Psychiatry 2009;48:71-8).

According to that study, Dr. Wagner said, “If by week 4, they haven't had a 58% improvement–if they're not more than 50% improved–they're unlikely to go on to remit. It's time to up the dose or switch.”

A successful therapy should be maintained for at least a year before attempting to cease treatment, Dr. Wagner said (J. Child. Adolesc. Psychopharmacol. 2008;18:389-94). “A year from the time you start treatment would be a bare minimum. I know a lot of parents want it short, but then it's important that they understand and assume the risk,” she said.

As to the box warnings on suicide risk that were issued by the FDA in 2004 and 2007, she referred to findings that showed a 44% decrease in primary care providers' diagnoses of depression after the warnings were issued and a 10% reduction in prescriptions of SSRIs (Arch. Gen. Psychiatry 2009;66:633-9).

“Where did those children who were previously being diagnosed with depression go?” Dr. Wagner asked. “The suicide rate is now 5% higher than it has been in the previous 20 years. It's worrisome that diagnosis … and treatment has dropped. There's increasing evidence that those trends could be an unintended consequence of the FDA's box warning.”

She concluded by citing another study that showed that the number of children needed to treat with antidepressants to achieve one remission is 10, while the comparable number needed to harm due to suicidal ideation or attempts is 112 (JAMA 2007;297:1683-96).

“That's not committing suicide but having suicidal attempts or ideation,” she emphasized. “They are 11 times more likely to get benefit than to develop suicidality. From my perspective, that's an excellent ratio.”

Dr. Wagner disclosed that she has received honorarium and travel support from AACAP, research support from National Institute of Mental Health, and other support from the American Society of Clinical Pharmacology.

NEW YORK – Sticking with medications that have shown positive results in randomized trials is important when it comes to treating pediatric depression, according to Dr. Karen Dineen Wagner.

The Food Drug Administration has approved only two drugs for treatment of pediatric depression–fluoxetine for patients aged 8 to 17 years, and escitalopram for those aged 12 to 17–but she pointed out that citalopram also showed positive results in a published trial, and that sertraline has shown positive results in ages 6 to 17 in an a priori pooled analysis of two studies (even though the individual trials were negative).

“Keep within those we know about,” Dr. Wagner advised at a pharmacology update, sponsored by the American Academy of Child and Adolescent Psychiatry (AACAP). She pointed out that budeprion, although widely prescribed, has not been shown effective in any published trial of a pediatric population. “Some parents want to know: Is this drug FDA approved [for use in children]? If you use medications that are not FDA-approved, you want to stay as best you can with those that have shown some efficacy [for use] in children, in the age group you're treating.”

Dr. Wagner said the only published trial of omega-3 fatty acids in prepubertal depression was small–involving 28 children–and while 70% of those in the treatment arm showed at least a 50% improvement, none of those on placebo did so (Am. J. Psychiatry 2006;163:1098-100).<

“Never in any study I've been involved in has there been a zero placebo response rate,” said Dr. Wagner, who is the Marie B. Gale Centennial Professor and vice chairwoman of the department of psychiatry and behavior sciences at the University of Texas Medical Branch in Galveston. “But who knows? It was published.”

Many of the trials that failed to show positive results, she said, did so not because the treatment arms showed low response rates, but because the placebo arms showed high improvement rates.

“What makes the placebo response rates so high in children?” Dr. Wagner asked. She cited a recent meta-analysis showing that the chief predictor of a high placebo response rate is the number of study sites (Am. J. Psychiatry 2009;166:42-9).

“Another predictor of a high placebo response rate is the baseline of severity. If a child is enrolled with moderate depression, it's very likely they'll respond to placebo as well as to medication.”

Although the Treatment for Adolescents With Depression Study (TADS) showed that cognitive-behavioral therapy (CBT) can be as effective as medication in improving symptoms at 36 weeks, Dr. Wagner noted that it was less effective at 12 weeks (Arch. Gen. Psychiatry 2007;64:1132-44; Am. J. Psychiatry 2009;166:337-44).<

“What [the study] shows is that CBT is effective, but it takes a while to work,” she said. “Parents have to be advised about that. Some will get better early, but for the most part it will take time. The medication will work faster. For moderate to severe depression, CBT just may take too long.”

She pointed to another analysis of TADS that found that the rate of attempted suicides or suicidal ideation between those on medication and those on placebo did not vary over the course of the study (J. Clin. Psychiatry 2009;70:741-7). “You would think if there was a drug effect, there would be a timing to it,” she said.

One of the key predictors of suicidal attempts or ideation in TADS was acute interpersonal conflict. “Usually, it was a fight or conflict with a parent,” Dr. Wagner said. “This needs to be discussed with parents. Keeping conflict low is important.”

In addressing the question of whether to switch to another selective serotonin reuptake inhibitor or to another class of drugs when an adolescent fails initial therapy, Dr. Wagner asked for a show of hands from the psychiatrists in attendance as to which strategy they would prefer.

“Everybody who raised their hand was correct,”she said, citing recent evidence from the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) trial (JAMA 2008;299:901-13). “If your child fails an SSRI, they have a 50% chance of doing well on another SSRI and a 50% chance of improvement on a different class. Adding CBT increases the chances of improvement by about 11%.”

Like TADS, the TORDIA trial also found that family conflict is a leading predictor of suicide attempts, as is baseline suicidal ideation.

“Ideation in the face of family conflict is a group to watch very carefully,” she emphasized.

Guidance on how long a clinician should wait before deciding whether an initial treatment needs to be changed or supplemented came from study that was published last year (J. Am. Acad. Child Adolesc. Psychiatry 2009;48:71-8).

According to that study, Dr. Wagner said, “If by week 4, they haven't had a 58% improvement–if they're not more than 50% improved–they're unlikely to go on to remit. It's time to up the dose or switch.”

A successful therapy should be maintained for at least a year before attempting to cease treatment, Dr. Wagner said (J. Child. Adolesc. Psychopharmacol. 2008;18:389-94). “A year from the time you start treatment would be a bare minimum. I know a lot of parents want it short, but then it's important that they understand and assume the risk,” she said.

As to the box warnings on suicide risk that were issued by the FDA in 2004 and 2007, she referred to findings that showed a 44% decrease in primary care providers' diagnoses of depression after the warnings were issued and a 10% reduction in prescriptions of SSRIs (Arch. Gen. Psychiatry 2009;66:633-9).

“Where did those children who were previously being diagnosed with depression go?” Dr. Wagner asked. “The suicide rate is now 5% higher than it has been in the previous 20 years. It's worrisome that diagnosis … and treatment has dropped. There's increasing evidence that those trends could be an unintended consequence of the FDA's box warning.”

She concluded by citing another study that showed that the number of children needed to treat with antidepressants to achieve one remission is 10, while the comparable number needed to harm due to suicidal ideation or attempts is 112 (JAMA 2007;297:1683-96).

“That's not committing suicide but having suicidal attempts or ideation,” she emphasized. “They are 11 times more likely to get benefit than to develop suicidality. From my perspective, that's an excellent ratio.”

Dr. Wagner disclosed that she has received honorarium and travel support from AACAP, research support from National Institute of Mental Health, and other support from the American Society of Clinical Pharmacology.

NEW YORK – A wealth of new data is emerging that will help clinicians anticipate and manage endocrine complications of psychotropic drugs, according to a leading researcher.

“We can't take a gene chip and come up with firm recommendations,” said Dr. Harold E. Carlson, who has published widely in the field as professor of medicine and endocrinology at Stony Brook (New York) University Health Sciences Center. But based on new data, he said, “We can think about individualized pharmacotherapy tailored to your patients' needs.”

Reduced height and weight in children and adolescents taking stimulants for attention-deficit/hyperactivity disorder (ADHD) has been a concern for years, and the latest data from the Multimodal Treatment of ADHD (MTA) Study suggest that growth deficits of about 1 inch persist after 8 years of treatment (J. Am. Acad. Child Adolesc. Psychiatry 2009;48:484-500.)

“We still do not have published data on the final adult height of children who have been treated continuously from childhood with stimulants,” Dr. Carlson said at a psychopharmacology update, sponsored by the American Academy of Child and Adolescent Psychiatry (AACAP). “The MTA study is nearing the point where most of the subjects will reach their final adult type. So far, [co–principal investigator] Jim Swanson tells me they remain about 1 inch shorter than they should otherwise be. They may wind up with a permanent growth deficit.”

On the other hand, permanent growth deficits were not observed in a study of atomoxetine (J. Child Adolesc. Psychopharmacol. 2007;17:689-700). In the study of 61 children treated for 5 years, initial slowing of growth was followed by a period of catch-up, such that height was usually normal by the fourth or fifth year.

Individual characteristics of patients can alert clinicians to those who might be at increased risk of reduced growth, Dr. Carlson noted. Prepubertal children have more slowing of growth than do adolescents; boys have more slowing than do girls; and children who are tall or overweight at the inception of treatment are at greater risk of slowed growth than shorter, underweight children.

The bottom line, Dr. Carlson said, is that all children and adolescents need to have their height and weight measured before beginning stimulant treatment.

“Do it yourself, or get it from the pediatrician,” he said. “Get the growth charts. And then someone should measure height and weight every 6 to 12 months. If the kid seems to be falling off his or her growth curve, and it's a substantial amount, then I think it's time to speak to the pediatrician and consider referring to a pediatric endocrinologist.”

Dr. Carlson urged physicians to use the lowest effective dose, to avoid giving short-acting stimulants just before meals, and to provide high-energy snacks or meals when the appetite is least suppressed.

“Work with the family,” he said. “If the kids' last dose is in the late afternoon, try having them give a wonderful bedtime snack.”

The opposite metabolic effect–weight gain associated with antipsychotics–has been confirmed in multiple studies cited by Dr. Carlson, including one study (J. Am. Acad. Child Adolesc. Psychiatry 2002;413:337-43) showing that olanzapine and risperidone are both associated with “extreme” weight gain in adolescents. The best defense against such unwanted effects, he said, is a good offense.

“You're going to want to calculate the child's BMI before you begin treatment, and then monitor it at every visit,” he said. “Provide counseling on diet and exercise from the start. It's much harder to take it off than to prevent it. Structured programs work best. If weight is progressing quickly, try switching medications to one less associated with weight gain. In resistant cases, pharmaceutical therapies have been used to promote weight loss, such as orlistat or metformin.”

Sudden cardiac death is another risk to consider when prescribing stimulant medications for ADHD, Dr. Carlson noted.

Confusion has ensued from the varying recommendations for and against routine ECGs by the American Heart Association, the American Academy of Pediatrics, and the AACAP; however “All three groups agree you need a good cardiac history, a detailed family history, and a careful physical exam,” Dr. Carlson said. “All agree an ECG should be performed if the initial valuation suggested increased cardiac risk, but the ECG does not need to be done in the absence of such findings.”

Despite the growing consensus, he added, “We're not at the end of the story yet.” The fact is, Dr. Carlson pointed out, no firm data have yet established whether or not ADHD medications truly do increase the risk of sudden cardiac death, and if so, by how much.

“Looking at all the data we do have,” he said, “it certainly seems like the risk is low, about one death per 100,000 per year.”

However, in what Dr. Carlson described as “the earthquake of several months ago,” a case-control study found that youths who died of sudden cardiac death were 7.4 times more likely to be taking stimulants for ADHD than were youths who died as passengers in automobile accents (Am. J. Psychiatry 2009;166:992-1001).

“The study had a bunch of flaws, pointed out in editorials and letters since,” Dr. Carlson noted. “The FDA has not changed its policy as a result.”

With a large study now underway aimed at replicating the data in that 2009 study, Dr. Carlson said, “I would surely hope that with an n of 100,000, we should get a good answer. So stay tuned.”

Another endocrine risk reviewed by Dr. Carlson was the stimulation of excess prolactin associated with antipsychotics, a condition that not only stimulates lactation but also can inhibit penile erections, decrease libido, and cause a variety of other adverse effects.

Dr. Carlson cited unpublished data from a study by Dr. Christoph U. Correll, showing that the 3-month incidence of missing at least one menstrual period in 152 female youths varied widely, from 21.7% on olanzapine, and 30% on risperidone, to 2.9% on quetiapine and 8.3% of aripiprazole. Risperidone also had the highest incidence, at 6.3%, associated with galactorrhea in 345 postpubertal youth.

“You need to ask your patients about these potential side effects,” Dr. Carlson said. “A lot of teenagers will not volunteer this information. You'll have to drag it out of them little by little. All of these things are sensitive issues in teenagers.”

If signs and symptoms of hyperprolactinemia are confirmed by a blood test, switching to a more prolactin-sparing agent, or reducing the dose, are recommended. But, he added, “If you can't stop or switch, you can combine your drug with one that is prolactin neutral or lowering, such as aripiprazole.” He cited a paper (Am. J. Psychiatry 2007;164:1404-10) that found that adjunctive aripiprazole treatment reversed hyperprolactinemia in both sexes.

Finally, Dr. Carlson noted that the incidence of polycystic ovary syndrome (PCOS) was found to be 10.5% in bipolar patients taking valproate, compared with 1.4% of those taking any other antipsychotic medication (Biol. Psychiatry 2006;59:1078-86).

With all female bipolar patients, he said, “Ask about their menstrual function,” Dr. Carlson recommended. “Ask before starting a drug and then each time you see them. Ask about acne and facial or body hair. They're not going to volunteer this very often.”

If symptoms of PCOS emerge, he said: “Arrange for them to get counseling on diet and exercise. You could set them up to see a primary care physician, gynecologist, or endocrinologist. There are treatments besides stopping the drug.”

Dr. Carlson disclosed financial relationships with pharmaceutical companies, including Eli Lilly; Janssen L.P.; Ortho-McNeil-Janssen Pharmaceuticals; Otsuka America Pharmaceutical; Bristol-Myers Squibb; Cephalon Inc.; McNeil Pediatrics, a division of McNeil-PPC; and Shire U.S.

NEW YORK – A wealth of new data is emerging that will help clinicians anticipate and manage endocrine complications of psychotropic drugs, according to a leading researcher.

“We can't take a gene chip and come up with firm recommendations,” said Dr. Harold E. Carlson, who has published widely in the field as professor of medicine and endocrinology at Stony Brook (New York) University Health Sciences Center. But based on new data, he said, “We can think about individualized pharmacotherapy tailored to your patients' needs.”

Reduced height and weight in children and adolescents taking stimulants for attention-deficit/hyperactivity disorder (ADHD) has been a concern for years, and the latest data from the Multimodal Treatment of ADHD (MTA) Study suggest that growth deficits of about 1 inch persist after 8 years of treatment (J. Am. Acad. Child Adolesc. Psychiatry 2009;48:484-500.)

“We still do not have published data on the final adult height of children who have been treated continuously from childhood with stimulants,” Dr. Carlson said at a psychopharmacology update, sponsored by the American Academy of Child and Adolescent Psychiatry (AACAP). “The MTA study is nearing the point where most of the subjects will reach their final adult type. So far, [co–principal investigator] Jim Swanson tells me they remain about 1 inch shorter than they should otherwise be. They may wind up with a permanent growth deficit.”

On the other hand, permanent growth deficits were not observed in a study of atomoxetine (J. Child Adolesc. Psychopharmacol. 2007;17:689-700). In the study of 61 children treated for 5 years, initial slowing of growth was followed by a period of catch-up, such that height was usually normal by the fourth or fifth year.

Individual characteristics of patients can alert clinicians to those who might be at increased risk of reduced growth, Dr. Carlson noted. Prepubertal children have more slowing of growth than do adolescents; boys have more slowing than do girls; and children who are tall or overweight at the inception of treatment are at greater risk of slowed growth than shorter, underweight children.

The bottom line, Dr. Carlson said, is that all children and adolescents need to have their height and weight measured before beginning stimulant treatment.

“Do it yourself, or get it from the pediatrician,” he said. “Get the growth charts. And then someone should measure height and weight every 6 to 12 months. If the kid seems to be falling off his or her growth curve, and it's a substantial amount, then I think it's time to speak to the pediatrician and consider referring to a pediatric endocrinologist.”

Dr. Carlson urged physicians to use the lowest effective dose, to avoid giving short-acting stimulants just before meals, and to provide high-energy snacks or meals when the appetite is least suppressed.

“Work with the family,” he said. “If the kids' last dose is in the late afternoon, try having them give a wonderful bedtime snack.”

The opposite metabolic effect–weight gain associated with antipsychotics–has been confirmed in multiple studies cited by Dr. Carlson, including one study (J. Am. Acad. Child Adolesc. Psychiatry 2002;413:337-43) showing that olanzapine and risperidone are both associated with “extreme” weight gain in adolescents. The best defense against such unwanted effects, he said, is a good offense.

“You're going to want to calculate the child's BMI before you begin treatment, and then monitor it at every visit,” he said. “Provide counseling on diet and exercise from the start. It's much harder to take it off than to prevent it. Structured programs work best. If weight is progressing quickly, try switching medications to one less associated with weight gain. In resistant cases, pharmaceutical therapies have been used to promote weight loss, such as orlistat or metformin.”

Sudden cardiac death is another risk to consider when prescribing stimulant medications for ADHD, Dr. Carlson noted.

Confusion has ensued from the varying recommendations for and against routine ECGs by the American Heart Association, the American Academy of Pediatrics, and the AACAP; however “All three groups agree you need a good cardiac history, a detailed family history, and a careful physical exam,” Dr. Carlson said. “All agree an ECG should be performed if the initial valuation suggested increased cardiac risk, but the ECG does not need to be done in the absence of such findings.”

Despite the growing consensus, he added, “We're not at the end of the story yet.” The fact is, Dr. Carlson pointed out, no firm data have yet established whether or not ADHD medications truly do increase the risk of sudden cardiac death, and if so, by how much.

“Looking at all the data we do have,” he said, “it certainly seems like the risk is low, about one death per 100,000 per year.”

However, in what Dr. Carlson described as “the earthquake of several months ago,” a case-control study found that youths who died of sudden cardiac death were 7.4 times more likely to be taking stimulants for ADHD than were youths who died as passengers in automobile accents (Am. J. Psychiatry 2009;166:992-1001).

“The study had a bunch of flaws, pointed out in editorials and letters since,” Dr. Carlson noted. “The FDA has not changed its policy as a result.”

With a large study now underway aimed at replicating the data in that 2009 study, Dr. Carlson said, “I would surely hope that with an n of 100,000, we should get a good answer. So stay tuned.”

Another endocrine risk reviewed by Dr. Carlson was the stimulation of excess prolactin associated with antipsychotics, a condition that not only stimulates lactation but also can inhibit penile erections, decrease libido, and cause a variety of other adverse effects.

Dr. Carlson cited unpublished data from a study by Dr. Christoph U. Correll, showing that the 3-month incidence of missing at least one menstrual period in 152 female youths varied widely, from 21.7% on olanzapine, and 30% on risperidone, to 2.9% on quetiapine and 8.3% of aripiprazole. Risperidone also had the highest incidence, at 6.3%, associated with galactorrhea in 345 postpubertal youth.

“You need to ask your patients about these potential side effects,” Dr. Carlson said. “A lot of teenagers will not volunteer this information. You'll have to drag it out of them little by little. All of these things are sensitive issues in teenagers.”

If signs and symptoms of hyperprolactinemia are confirmed by a blood test, switching to a more prolactin-sparing agent, or reducing the dose, are recommended. But, he added, “If you can't stop or switch, you can combine your drug with one that is prolactin neutral or lowering, such as aripiprazole.” He cited a paper (Am. J. Psychiatry 2007;164:1404-10) that found that adjunctive aripiprazole treatment reversed hyperprolactinemia in both sexes.

Finally, Dr. Carlson noted that the incidence of polycystic ovary syndrome (PCOS) was found to be 10.5% in bipolar patients taking valproate, compared with 1.4% of those taking any other antipsychotic medication (Biol. Psychiatry 2006;59:1078-86).

With all female bipolar patients, he said, “Ask about their menstrual function,” Dr. Carlson recommended. “Ask before starting a drug and then each time you see them. Ask about acne and facial or body hair. They're not going to volunteer this very often.”

If symptoms of PCOS emerge, he said: “Arrange for them to get counseling on diet and exercise. You could set them up to see a primary care physician, gynecologist, or endocrinologist. There are treatments besides stopping the drug.”

Dr. Carlson disclosed financial relationships with pharmaceutical companies, including Eli Lilly; Janssen L.P.; Ortho-McNeil-Janssen Pharmaceuticals; Otsuka America Pharmaceutical; Bristol-Myers Squibb; Cephalon Inc.; McNeil Pediatrics, a division of McNeil-PPC; and Shire U.S.

NEW YORK – A wealth of new data is emerging that will help clinicians anticipate and manage endocrine complications of psychotropic drugs, according to a leading researcher.

“We can't take a gene chip and come up with firm recommendations,” said Dr. Harold E. Carlson, who has published widely in the field as professor of medicine and endocrinology at Stony Brook (New York) University Health Sciences Center. But based on new data, he said, “We can think about individualized pharmacotherapy tailored to your patients' needs.”

Reduced height and weight in children and adolescents taking stimulants for attention-deficit/hyperactivity disorder (ADHD) has been a concern for years, and the latest data from the Multimodal Treatment of ADHD (MTA) Study suggest that growth deficits of about 1 inch persist after 8 years of treatment (J. Am. Acad. Child Adolesc. Psychiatry 2009;48:484-500.)

“We still do not have published data on the final adult height of children who have been treated continuously from childhood with stimulants,” Dr. Carlson said at a psychopharmacology update, sponsored by the American Academy of Child and Adolescent Psychiatry (AACAP). “The MTA study is nearing the point where most of the subjects will reach their final adult type. So far, [co–principal investigator] Jim Swanson tells me they remain about 1 inch shorter than they should otherwise be. They may wind up with a permanent growth deficit.”

On the other hand, permanent growth deficits were not observed in a study of atomoxetine (J. Child Adolesc. Psychopharmacol. 2007;17:689-700). In the study of 61 children treated for 5 years, initial slowing of growth was followed by a period of catch-up, such that height was usually normal by the fourth or fifth year.

Individual characteristics of patients can alert clinicians to those who might be at increased risk of reduced growth, Dr. Carlson noted. Prepubertal children have more slowing of growth than do adolescents; boys have more slowing than do girls; and children who are tall or overweight at the inception of treatment are at greater risk of slowed growth than shorter, underweight children.

The bottom line, Dr. Carlson said, is that all children and adolescents need to have their height and weight measured before beginning stimulant treatment.

“Do it yourself, or get it from the pediatrician,” he said. “Get the growth charts. And then someone should measure height and weight every 6 to 12 months. If the kid seems to be falling off his or her growth curve, and it's a substantial amount, then I think it's time to speak to the pediatrician and consider referring to a pediatric endocrinologist.”

Dr. Carlson urged physicians to use the lowest effective dose, to avoid giving short-acting stimulants just before meals, and to provide high-energy snacks or meals when the appetite is least suppressed.

“Work with the family,” he said. “If the kids' last dose is in the late afternoon, try having them give a wonderful bedtime snack.”

The opposite metabolic effect–weight gain associated with antipsychotics–has been confirmed in multiple studies cited by Dr. Carlson, including one study (J. Am. Acad. Child Adolesc. Psychiatry 2002;413:337-43) showing that olanzapine and risperidone are both associated with “extreme” weight gain in adolescents. The best defense against such unwanted effects, he said, is a good offense.

“You're going to want to calculate the child's BMI before you begin treatment, and then monitor it at every visit,” he said. “Provide counseling on diet and exercise from the start. It's much harder to take it off than to prevent it. Structured programs work best. If weight is progressing quickly, try switching medications to one less associated with weight gain. In resistant cases, pharmaceutical therapies have been used to promote weight loss, such as orlistat or metformin.”

Sudden cardiac death is another risk to consider when prescribing stimulant medications for ADHD, Dr. Carlson noted.

Confusion has ensued from the varying recommendations for and against routine ECGs by the American Heart Association, the American Academy of Pediatrics, and the AACAP; however “All three groups agree you need a good cardiac history, a detailed family history, and a careful physical exam,” Dr. Carlson said. “All agree an ECG should be performed if the initial valuation suggested increased cardiac risk, but the ECG does not need to be done in the absence of such findings.”

Despite the growing consensus, he added, “We're not at the end of the story yet.” The fact is, Dr. Carlson pointed out, no firm data have yet established whether or not ADHD medications truly do increase the risk of sudden cardiac death, and if so, by how much.

“Looking at all the data we do have,” he said, “it certainly seems like the risk is low, about one death per 100,000 per year.”

However, in what Dr. Carlson described as “the earthquake of several months ago,” a case-control study found that youths who died of sudden cardiac death were 7.4 times more likely to be taking stimulants for ADHD than were youths who died as passengers in automobile accents (Am. J. Psychiatry 2009;166:992-1001).

“The study had a bunch of flaws, pointed out in editorials and letters since,” Dr. Carlson noted. “The FDA has not changed its policy as a result.”

With a large study now underway aimed at replicating the data in that 2009 study, Dr. Carlson said, “I would surely hope that with an n of 100,000, we should get a good answer. So stay tuned.”

Another endocrine risk reviewed by Dr. Carlson was the stimulation of excess prolactin associated with antipsychotics, a condition that not only stimulates lactation but also can inhibit penile erections, decrease libido, and cause a variety of other adverse effects.

Dr. Carlson cited unpublished data from a study by Dr. Christoph U. Correll, showing that the 3-month incidence of missing at least one menstrual period in 152 female youths varied widely, from 21.7% on olanzapine, and 30% on risperidone, to 2.9% on quetiapine and 8.3% of aripiprazole. Risperidone also had the highest incidence, at 6.3%, associated with galactorrhea in 345 postpubertal youth.

“You need to ask your patients about these potential side effects,” Dr. Carlson said. “A lot of teenagers will not volunteer this information. You'll have to drag it out of them little by little. All of these things are sensitive issues in teenagers.”

If signs and symptoms of hyperprolactinemia are confirmed by a blood test, switching to a more prolactin-sparing agent, or reducing the dose, are recommended. But, he added, “If you can't stop or switch, you can combine your drug with one that is prolactin neutral or lowering, such as aripiprazole.” He cited a paper (Am. J. Psychiatry 2007;164:1404-10) that found that adjunctive aripiprazole treatment reversed hyperprolactinemia in both sexes.

Finally, Dr. Carlson noted that the incidence of polycystic ovary syndrome (PCOS) was found to be 10.5% in bipolar patients taking valproate, compared with 1.4% of those taking any other antipsychotic medication (Biol. Psychiatry 2006;59:1078-86).

With all female bipolar patients, he said, “Ask about their menstrual function,” Dr. Carlson recommended. “Ask before starting a drug and then each time you see them. Ask about acne and facial or body hair. They're not going to volunteer this very often.”

If symptoms of PCOS emerge, he said: “Arrange for them to get counseling on diet and exercise. You could set them up to see a primary care physician, gynecologist, or endocrinologist. There are treatments besides stopping the drug.”

Dr. Carlson disclosed financial relationships with pharmaceutical companies, including Eli Lilly; Janssen L.P.; Ortho-McNeil-Janssen Pharmaceuticals; Otsuka America Pharmaceutical; Bristol-Myers Squibb; Cephalon Inc.; McNeil Pediatrics, a division of McNeil-PPC; and Shire U.S.

Disclosures: The Calcium for Preeclampsia Prevention trial and the substudy presented here were funded by the National Institutes of Health. The substudy of the Nord-Trondelag Health Study was supported by the Norwegian University of Science and Technology and by the Central Norway Regional Health Authority. One of the investigators has financial ties to several pharmaceutical companies and has been named coinventor on several patents related to preeclampsia.

New evidence has strengthened the link between preeclampsia and reduced thyroid function during pregnancy, and has shown that the association persists for decades.

Women who have had preeclampsia should be monitored for reduced thyroid function after pregnancy, according to Dr. Richard J. Levine.

“We can't say for sure until we have some other studies out there that will link it more tightly,” Dr. Levine of the National Institute of Child Health and Human Development's division of epidemiology, statistics, and prevention research, said in an interview. “But I think it's worthwhile to look for reduced thyroid function in these women now. It's such an easy test to do, and the treatment is so cheap. I think it should be done.”

In an article published online in BMJ, two separate studies were reported (2009 Nov. 17 [doi:10.1136/bmj.b4336]). In the first Dr. Levine and his colleagues examined stored blood samples from a U.S. trial, Calcium for Preeclampsia Prevention, to check TSH levels early and later in pregnancy, in a comparison of 141 women who developed preeclampsia with 141 controls.

Whereas TSH did not vary significantly between the two groups early in pregnancy, by the time of delivery, those who developed preeclampsia had twice the risk of exhibiting high TSH levels, compared with controls.

Moreover, the increase in TSH level was significantly associated with increasing quartiles of soluble fms-like tyrosine kinase 1 (sFlt-1), which “may be responsible for the clinical phenotype of preeclampsia,” the investigators wrote.

In the second study, Dr. Levine and his colleagues analyzed the Norwegian Nord-Trondelag Health Study of 7,121 women who had given birth to a first child in 1967 or later, and measurements of thyroid function 20 or more years later. They found that those who had preeclampsia in their first pregnancy were 70% more likely to have high thyroid-stimulating hormone concentrations years later than were women who had not had preeclampsia. Those who had preeclampsia in two pregnancies had a nearly sixfold increased risk of high TSH levels.

“Increased circulating concentrations of [sFlt-1], most notably after onset of preeclampsia, were associated with subtle abnormalities of the thyroid during pregnancy. “These in turn may predispose to the development of reduced thyroid function and possibly overt hypothyroidism in later life,” they wrote.

“The hypothesis is fascinating and has to be explored further,” said Dr. Marshall D. Lindheimer, professor emeritus of obstetrics and gynecology and of medicine at the University of Chicago.

Disclosures: The Calcium for Preeclampsia Prevention trial and the substudy presented here were funded by the National Institutes of Health. The substudy of the Nord-Trondelag Health Study was supported by the Norwegian University of Science and Technology and by the Central Norway Regional Health Authority. One of the investigators has financial ties to several pharmaceutical companies and has been named coinventor on several patents related to preeclampsia.

New evidence has strengthened the link between preeclampsia and reduced thyroid function during pregnancy, and has shown that the association persists for decades.

Women who have had preeclampsia should be monitored for reduced thyroid function after pregnancy, according to Dr. Richard J. Levine.

“We can't say for sure until we have some other studies out there that will link it more tightly,” Dr. Levine of the National Institute of Child Health and Human Development's division of epidemiology, statistics, and prevention research, said in an interview. “But I think it's worthwhile to look for reduced thyroid function in these women now. It's such an easy test to do, and the treatment is so cheap. I think it should be done.”

In an article published online in BMJ, two separate studies were reported (2009 Nov. 17 [doi:10.1136/bmj.b4336]). In the first Dr. Levine and his colleagues examined stored blood samples from a U.S. trial, Calcium for Preeclampsia Prevention, to check TSH levels early and later in pregnancy, in a comparison of 141 women who developed preeclampsia with 141 controls.

Whereas TSH did not vary significantly between the two groups early in pregnancy, by the time of delivery, those who developed preeclampsia had twice the risk of exhibiting high TSH levels, compared with controls.

Moreover, the increase in TSH level was significantly associated with increasing quartiles of soluble fms-like tyrosine kinase 1 (sFlt-1), which “may be responsible for the clinical phenotype of preeclampsia,” the investigators wrote.

In the second study, Dr. Levine and his colleagues analyzed the Norwegian Nord-Trondelag Health Study of 7,121 women who had given birth to a first child in 1967 or later, and measurements of thyroid function 20 or more years later. They found that those who had preeclampsia in their first pregnancy were 70% more likely to have high thyroid-stimulating hormone concentrations years later than were women who had not had preeclampsia. Those who had preeclampsia in two pregnancies had a nearly sixfold increased risk of high TSH levels.

“Increased circulating concentrations of [sFlt-1], most notably after onset of preeclampsia, were associated with subtle abnormalities of the thyroid during pregnancy. “These in turn may predispose to the development of reduced thyroid function and possibly overt hypothyroidism in later life,” they wrote.

“The hypothesis is fascinating and has to be explored further,” said Dr. Marshall D. Lindheimer, professor emeritus of obstetrics and gynecology and of medicine at the University of Chicago.

Disclosures: The Calcium for Preeclampsia Prevention trial and the substudy presented here were funded by the National Institutes of Health. The substudy of the Nord-Trondelag Health Study was supported by the Norwegian University of Science and Technology and by the Central Norway Regional Health Authority. One of the investigators has financial ties to several pharmaceutical companies and has been named coinventor on several patents related to preeclampsia.

New evidence has strengthened the link between preeclampsia and reduced thyroid function during pregnancy, and has shown that the association persists for decades.

Women who have had preeclampsia should be monitored for reduced thyroid function after pregnancy, according to Dr. Richard J. Levine.

“We can't say for sure until we have some other studies out there that will link it more tightly,” Dr. Levine of the National Institute of Child Health and Human Development's division of epidemiology, statistics, and prevention research, said in an interview. “But I think it's worthwhile to look for reduced thyroid function in these women now. It's such an easy test to do, and the treatment is so cheap. I think it should be done.”

In an article published online in BMJ, two separate studies were reported (2009 Nov. 17 [doi:10.1136/bmj.b4336]). In the first Dr. Levine and his colleagues examined stored blood samples from a U.S. trial, Calcium for Preeclampsia Prevention, to check TSH levels early and later in pregnancy, in a comparison of 141 women who developed preeclampsia with 141 controls.

Whereas TSH did not vary significantly between the two groups early in pregnancy, by the time of delivery, those who developed preeclampsia had twice the risk of exhibiting high TSH levels, compared with controls.

Moreover, the increase in TSH level was significantly associated with increasing quartiles of soluble fms-like tyrosine kinase 1 (sFlt-1), which “may be responsible for the clinical phenotype of preeclampsia,” the investigators wrote.

In the second study, Dr. Levine and his colleagues analyzed the Norwegian Nord-Trondelag Health Study of 7,121 women who had given birth to a first child in 1967 or later, and measurements of thyroid function 20 or more years later. They found that those who had preeclampsia in their first pregnancy were 70% more likely to have high thyroid-stimulating hormone concentrations years later than were women who had not had preeclampsia. Those who had preeclampsia in two pregnancies had a nearly sixfold increased risk of high TSH levels.

“Increased circulating concentrations of [sFlt-1], most notably after onset of preeclampsia, were associated with subtle abnormalities of the thyroid during pregnancy. “These in turn may predispose to the development of reduced thyroid function and possibly overt hypothyroidism in later life,” they wrote.

“The hypothesis is fascinating and has to be explored further,” said Dr. Marshall D. Lindheimer, professor emeritus of obstetrics and gynecology and of medicine at the University of Chicago.