ASCP 2011

BOCA RATON, FLA. – "Just what we need – another scale," Dr. Mark Zimmerman said, tongue-in-cheek, as he started to explain why he and his colleagues developed the Remission From Depression Questionnaire.

Current measures define remission based on a lack of depressive symptoms alone, which is insufficient, Dr. Zimmerman said at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

In a previous study of 514 depressed outpatients (J. Psychiatr. Res. 2008;42:797-801), "we found symptom resolution was not the most important consideration of depression remission," Dr. Zimmerman said. "Multiple factors were identified, so from a patient point of view, symptom-based definitions of remission are too narrow."

So Dr. Zimmerman and his colleagues developed the multidimensional Remission From Depression Questionnaire (RDQ), and conducted two studies to test reliability, validity, and patient preferences.

The RDQ assesses seven constructs: symptoms of depression, other symptoms, coping ability, positive mental health, functioning, life satisfaction, and general sense of well being. When the researchers compared remitters to nonremitters, significant differences were found on the RDQ total scale, depressive symptoms, and other symptoms. These findings support the RDQ as a valid measure, said Dr. Zimmerman, director of outpatient psychiatry at Rhode Island Hospital and with the department of psychiatry and human behavior at Brown University, both in Providence.

In the first study, Dr. Zimmerman and his colleagues compared responses from 102 depressed outpatients on the 41-item RDQ and the 16-item Quick Inventory of Depressive Symptomatology (QIDS). "They did not know we had developed one of these measures," he said.

There were no differences between the two measures on completion time. They were "equally burdensome and equally understandable," Dr. Zimmerman said.

Participants also reported their preference using a nine-item measure. Twice as many reported the RDQ more accurately described their overall state, 48%, vs. 24% for the QIDS. Nearly half said they preferred to complete the RDQ, 46%, compared with 22% who preferred completing the QIDS.

"Our conclusion from the first study is ... patients prefer the multifactorial RDQ scale more than a symptoms-based measure."

In a second study, the investigators asked 247 mildly depressed outpatients in ongoing treatment to complete the RDQ. The QIDS average score was 9.8, and the Hamilton Depression Rating Scale average score was 8.6. The RDQ correlated 0.62 with Hamilton scale and 0.70 with the Clinical Global Impression-Severity scale.

Dr. Zimmerman and his colleagues also split the cohort into remitters vs. nonremitters. Significant differences were found between these groups on the RDQ total score, 18 vs. 43; the depressive symptoms score, 5 vs. 12; and the other symptoms score, 2.8 vs. 5.7.

"The RDQ is a reliable and valid measure that evaluates multiple domains," Dr. Zimmerman said.

A group of 60 of the 247 patients waited and completed the RDQ measure a second time to test its reliability. The test-retest reliability and internal consistency were all greater than 0.8, Dr. Zimmerman said.

The next step is to assess the RDQ as an outcome measure in an acute treatment study of depression, Dr. Zimmerman said. An unanswered question is: Does the RDQ do a better job of predicting relapse compared to just a symptom-based scale?

Dr. Zimmerman said he had no disclosures. The studies were funded by Eli Lilly.

BOCA RATON, FLA. – "Just what we need – another scale," Dr. Mark Zimmerman said, tongue-in-cheek, as he started to explain why he and his colleagues developed the Remission From Depression Questionnaire.

Current measures define remission based on a lack of depressive symptoms alone, which is insufficient, Dr. Zimmerman said at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

In a previous study of 514 depressed outpatients (J. Psychiatr. Res. 2008;42:797-801), "we found symptom resolution was not the most important consideration of depression remission," Dr. Zimmerman said. "Multiple factors were identified, so from a patient point of view, symptom-based definitions of remission are too narrow."

So Dr. Zimmerman and his colleagues developed the multidimensional Remission From Depression Questionnaire (RDQ), and conducted two studies to test reliability, validity, and patient preferences.

The RDQ assesses seven constructs: symptoms of depression, other symptoms, coping ability, positive mental health, functioning, life satisfaction, and general sense of well being. When the researchers compared remitters to nonremitters, significant differences were found on the RDQ total scale, depressive symptoms, and other symptoms. These findings support the RDQ as a valid measure, said Dr. Zimmerman, director of outpatient psychiatry at Rhode Island Hospital and with the department of psychiatry and human behavior at Brown University, both in Providence.

In the first study, Dr. Zimmerman and his colleagues compared responses from 102 depressed outpatients on the 41-item RDQ and the 16-item Quick Inventory of Depressive Symptomatology (QIDS). "They did not know we had developed one of these measures," he said.

There were no differences between the two measures on completion time. They were "equally burdensome and equally understandable," Dr. Zimmerman said.

Participants also reported their preference using a nine-item measure. Twice as many reported the RDQ more accurately described their overall state, 48%, vs. 24% for the QIDS. Nearly half said they preferred to complete the RDQ, 46%, compared with 22% who preferred completing the QIDS.

"Our conclusion from the first study is ... patients prefer the multifactorial RDQ scale more than a symptoms-based measure."

In a second study, the investigators asked 247 mildly depressed outpatients in ongoing treatment to complete the RDQ. The QIDS average score was 9.8, and the Hamilton Depression Rating Scale average score was 8.6. The RDQ correlated 0.62 with Hamilton scale and 0.70 with the Clinical Global Impression-Severity scale.

Dr. Zimmerman and his colleagues also split the cohort into remitters vs. nonremitters. Significant differences were found between these groups on the RDQ total score, 18 vs. 43; the depressive symptoms score, 5 vs. 12; and the other symptoms score, 2.8 vs. 5.7.

"The RDQ is a reliable and valid measure that evaluates multiple domains," Dr. Zimmerman said.

A group of 60 of the 247 patients waited and completed the RDQ measure a second time to test its reliability. The test-retest reliability and internal consistency were all greater than 0.8, Dr. Zimmerman said.

The next step is to assess the RDQ as an outcome measure in an acute treatment study of depression, Dr. Zimmerman said. An unanswered question is: Does the RDQ do a better job of predicting relapse compared to just a symptom-based scale?

Dr. Zimmerman said he had no disclosures. The studies were funded by Eli Lilly.

BOCA RATON, FLA. – "Just what we need – another scale," Dr. Mark Zimmerman said, tongue-in-cheek, as he started to explain why he and his colleagues developed the Remission From Depression Questionnaire.

Current measures define remission based on a lack of depressive symptoms alone, which is insufficient, Dr. Zimmerman said at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

In a previous study of 514 depressed outpatients (J. Psychiatr. Res. 2008;42:797-801), "we found symptom resolution was not the most important consideration of depression remission," Dr. Zimmerman said. "Multiple factors were identified, so from a patient point of view, symptom-based definitions of remission are too narrow."

So Dr. Zimmerman and his colleagues developed the multidimensional Remission From Depression Questionnaire (RDQ), and conducted two studies to test reliability, validity, and patient preferences.

The RDQ assesses seven constructs: symptoms of depression, other symptoms, coping ability, positive mental health, functioning, life satisfaction, and general sense of well being. When the researchers compared remitters to nonremitters, significant differences were found on the RDQ total scale, depressive symptoms, and other symptoms. These findings support the RDQ as a valid measure, said Dr. Zimmerman, director of outpatient psychiatry at Rhode Island Hospital and with the department of psychiatry and human behavior at Brown University, both in Providence.

In the first study, Dr. Zimmerman and his colleagues compared responses from 102 depressed outpatients on the 41-item RDQ and the 16-item Quick Inventory of Depressive Symptomatology (QIDS). "They did not know we had developed one of these measures," he said.

There were no differences between the two measures on completion time. They were "equally burdensome and equally understandable," Dr. Zimmerman said.

Participants also reported their preference using a nine-item measure. Twice as many reported the RDQ more accurately described their overall state, 48%, vs. 24% for the QIDS. Nearly half said they preferred to complete the RDQ, 46%, compared with 22% who preferred completing the QIDS.

"Our conclusion from the first study is ... patients prefer the multifactorial RDQ scale more than a symptoms-based measure."

In a second study, the investigators asked 247 mildly depressed outpatients in ongoing treatment to complete the RDQ. The QIDS average score was 9.8, and the Hamilton Depression Rating Scale average score was 8.6. The RDQ correlated 0.62 with Hamilton scale and 0.70 with the Clinical Global Impression-Severity scale.

Dr. Zimmerman and his colleagues also split the cohort into remitters vs. nonremitters. Significant differences were found between these groups on the RDQ total score, 18 vs. 43; the depressive symptoms score, 5 vs. 12; and the other symptoms score, 2.8 vs. 5.7.

"The RDQ is a reliable and valid measure that evaluates multiple domains," Dr. Zimmerman said.

A group of 60 of the 247 patients waited and completed the RDQ measure a second time to test its reliability. The test-retest reliability and internal consistency were all greater than 0.8, Dr. Zimmerman said.

The next step is to assess the RDQ as an outcome measure in an acute treatment study of depression, Dr. Zimmerman said. An unanswered question is: Does the RDQ do a better job of predicting relapse compared to just a symptom-based scale?

Dr. Zimmerman said he had no disclosures. The studies were funded by Eli Lilly.

BOCA RATON, FLA. – Not all agents available to detoxify a person with a heroin addiction are created equal.

In a prospective comparison study, people who took buprenorphine experienced significantly fewer withdrawal symptoms and fewer serious adverse events over 10 days, compared with detoxification with tramadol.

Previous retrospective studies showed that buprenorphine was more effective than tramadol for acute heroin withdrawal, Dr. Jatinder M. Chawla said (Am. J. Addict. 2006;15:186-91; J. Addict. Dis. 2003;22:5-12). However, "there are some problems with buprenorphine," such as more abuse potential and a greater risk for respiratory depression, compared with tramadol, said Dr. Chawla, a psychiatry resident at SUNY Downstate Medical Center in Brooklyn, N.Y.

Also, tramadol is easier to administer in an outpatient setting because it’s an oral, nonscheduled medication compared with the sublingual, schedule III buprenorphine.

"We wanted to look at this in a prospective study," Dr. Chawla said in an interview at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

Dr. Chawla and his associates assessed 62 men with a diagnosis of opiate dependence syndrome who had been admitted to the National Drug Dependence Treatment Centre in New Delhi, India. They were equally randomized to 10 days of buprenorphine or tramadol. Participants were aged 20-45 years. In all, 39 patients completed the 10-day study and were assessed further. Retention was not significantly different, with 21 buprenorphine and 18 tramadol patients remaining until study end.

No significant differences were found between groups in baseline Addiction Severity Index score; mean age of initiation of heroin use; duration of daily use; or average intake of heroin in the past month.

However, the researchers did find significant differences on the Subjective (SOWS) and Objective Opioid Withdrawal Scale (OOWS) scores. For example, the mean SOWS score was significantly lower in the buprenorphine group on the second, third, and ninth days of detoxification (suggesting greater efficacy). In addition, the mean OOWS score was significantly lower on days 2 and 3 in the buprenorphine group, compared with the tramadol group.

Participants also completed a visual analog scale daily to rate their satisfaction with treatment. Again, on days 2 and 3 of detoxification, people taking buprenorphine rated their satisfaction significantly higher than those taking tramadol.

Three patients in the tramadol group experienced seizures. "Tramadol has the risk of inducing seizures at higher doses," Dr. Chawla said. The seizures occurred on days 4 and 6, when drug was tapered up to a higher dose, he added.

Nausea and dizziness also were reported by people in the tramadol group. Headache, drowsiness, and dizziness were the most common adverse event reports in the buprenorphine group.

Despite these findings, Dr. Chawla said that tramadol still has advantages over buprenorphine and is not absolutely contraindicated. Additional caution is warranted for people with a history of seizures. Tramadol could be an option for patients with mild to moderate heroin dependence who are at risk of becoming addicted to buprenorphine, he said. In addition, a lower dose of tramadol could potentially minimize adverse events.

A small sample size and data from a single center are potential limitations of the study, Dr. Chawla said.

The study was unfunded. Dr. Chawla received a New Investigator Award at the NCDEU meeting for this study. He said he had no relevant financial disclosures.

BOCA RATON, FLA. – Not all agents available to detoxify a person with a heroin addiction are created equal.

In a prospective comparison study, people who took buprenorphine experienced significantly fewer withdrawal symptoms and fewer serious adverse events over 10 days, compared with detoxification with tramadol.

Previous retrospective studies showed that buprenorphine was more effective than tramadol for acute heroin withdrawal, Dr. Jatinder M. Chawla said (Am. J. Addict. 2006;15:186-91; J. Addict. Dis. 2003;22:5-12). However, "there are some problems with buprenorphine," such as more abuse potential and a greater risk for respiratory depression, compared with tramadol, said Dr. Chawla, a psychiatry resident at SUNY Downstate Medical Center in Brooklyn, N.Y.

Also, tramadol is easier to administer in an outpatient setting because it’s an oral, nonscheduled medication compared with the sublingual, schedule III buprenorphine.

"We wanted to look at this in a prospective study," Dr. Chawla said in an interview at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

Dr. Chawla and his associates assessed 62 men with a diagnosis of opiate dependence syndrome who had been admitted to the National Drug Dependence Treatment Centre in New Delhi, India. They were equally randomized to 10 days of buprenorphine or tramadol. Participants were aged 20-45 years. In all, 39 patients completed the 10-day study and were assessed further. Retention was not significantly different, with 21 buprenorphine and 18 tramadol patients remaining until study end.

No significant differences were found between groups in baseline Addiction Severity Index score; mean age of initiation of heroin use; duration of daily use; or average intake of heroin in the past month.

However, the researchers did find significant differences on the Subjective (SOWS) and Objective Opioid Withdrawal Scale (OOWS) scores. For example, the mean SOWS score was significantly lower in the buprenorphine group on the second, third, and ninth days of detoxification (suggesting greater efficacy). In addition, the mean OOWS score was significantly lower on days 2 and 3 in the buprenorphine group, compared with the tramadol group.

Participants also completed a visual analog scale daily to rate their satisfaction with treatment. Again, on days 2 and 3 of detoxification, people taking buprenorphine rated their satisfaction significantly higher than those taking tramadol.

Three patients in the tramadol group experienced seizures. "Tramadol has the risk of inducing seizures at higher doses," Dr. Chawla said. The seizures occurred on days 4 and 6, when drug was tapered up to a higher dose, he added.

Nausea and dizziness also were reported by people in the tramadol group. Headache, drowsiness, and dizziness were the most common adverse event reports in the buprenorphine group.

Despite these findings, Dr. Chawla said that tramadol still has advantages over buprenorphine and is not absolutely contraindicated. Additional caution is warranted for people with a history of seizures. Tramadol could be an option for patients with mild to moderate heroin dependence who are at risk of becoming addicted to buprenorphine, he said. In addition, a lower dose of tramadol could potentially minimize adverse events.

A small sample size and data from a single center are potential limitations of the study, Dr. Chawla said.

The study was unfunded. Dr. Chawla received a New Investigator Award at the NCDEU meeting for this study. He said he had no relevant financial disclosures.

BOCA RATON, FLA. – Not all agents available to detoxify a person with a heroin addiction are created equal.

In a prospective comparison study, people who took buprenorphine experienced significantly fewer withdrawal symptoms and fewer serious adverse events over 10 days, compared with detoxification with tramadol.

Previous retrospective studies showed that buprenorphine was more effective than tramadol for acute heroin withdrawal, Dr. Jatinder M. Chawla said (Am. J. Addict. 2006;15:186-91; J. Addict. Dis. 2003;22:5-12). However, "there are some problems with buprenorphine," such as more abuse potential and a greater risk for respiratory depression, compared with tramadol, said Dr. Chawla, a psychiatry resident at SUNY Downstate Medical Center in Brooklyn, N.Y.

Also, tramadol is easier to administer in an outpatient setting because it’s an oral, nonscheduled medication compared with the sublingual, schedule III buprenorphine.

"We wanted to look at this in a prospective study," Dr. Chawla said in an interview at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

Dr. Chawla and his associates assessed 62 men with a diagnosis of opiate dependence syndrome who had been admitted to the National Drug Dependence Treatment Centre in New Delhi, India. They were equally randomized to 10 days of buprenorphine or tramadol. Participants were aged 20-45 years. In all, 39 patients completed the 10-day study and were assessed further. Retention was not significantly different, with 21 buprenorphine and 18 tramadol patients remaining until study end.

No significant differences were found between groups in baseline Addiction Severity Index score; mean age of initiation of heroin use; duration of daily use; or average intake of heroin in the past month.

However, the researchers did find significant differences on the Subjective (SOWS) and Objective Opioid Withdrawal Scale (OOWS) scores. For example, the mean SOWS score was significantly lower in the buprenorphine group on the second, third, and ninth days of detoxification (suggesting greater efficacy). In addition, the mean OOWS score was significantly lower on days 2 and 3 in the buprenorphine group, compared with the tramadol group.

Participants also completed a visual analog scale daily to rate their satisfaction with treatment. Again, on days 2 and 3 of detoxification, people taking buprenorphine rated their satisfaction significantly higher than those taking tramadol.

Three patients in the tramadol group experienced seizures. "Tramadol has the risk of inducing seizures at higher doses," Dr. Chawla said. The seizures occurred on days 4 and 6, when drug was tapered up to a higher dose, he added.

Nausea and dizziness also were reported by people in the tramadol group. Headache, drowsiness, and dizziness were the most common adverse event reports in the buprenorphine group.

Despite these findings, Dr. Chawla said that tramadol still has advantages over buprenorphine and is not absolutely contraindicated. Additional caution is warranted for people with a history of seizures. Tramadol could be an option for patients with mild to moderate heroin dependence who are at risk of becoming addicted to buprenorphine, he said. In addition, a lower dose of tramadol could potentially minimize adverse events.

A small sample size and data from a single center are potential limitations of the study, Dr. Chawla said.

The study was unfunded. Dr. Chawla received a New Investigator Award at the NCDEU meeting for this study. He said he had no relevant financial disclosures.

BOCA RATON, FLA. – Social withdrawal and irritability significantly improved when children with autism spectrum disorder took arbaclofen, a new medication in development, according to an open label, multicenter study.

Boosted by promising results with arbaclofen in fragile X syndrome – the leading known cause of inherited autism spectrum disorder (ASD) – Dr. Jeremy M. Veenstra-VanderWeele and his associates launched a study with 32 children and adolescents.

This is the first step to determine whether the GABA-B agonist would help people with ASD who do not have fragile X syndrome, Dr. Veenstra-VanderWeele said in an interview at the annual meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

Children showed significant improvement on the Aberrant Behavior Checklist social withdrawal subscale, from a mean 18.1 at baseline to 12.6 after 8 weeks, based on an intent-to-treat analysis. In addition, the researchers rated more than half – 20 of the 32 kids – as "much improved" or "very much improved" on the Clinical Global Impression for Improvement measure.

At the same time, mean scores on the Aberrant Behavior Checklist Irritability subscale significantly improved from 24.7 to 17.3.

"We saw a lot of promising improvements in people who were taking the medicine," said Dr. Veenstra-VanderWeele, assistant professor in psychiatry at Vanderbilt University in Nashville.

"We did see some adverse events, as you would expect. None of these were terribly severe, and most of them looked similar to fluctuations in peoples’ baseline behavior," Dr. Veenstra-VanderWeele said. One severe adverse event was increased aggression during a planned taper of arbaclofen.

"The medicine was very well tolerated, especially in contrast to available medicines in autism, which, unfortunately, can have significant side effects," Dr. Veenstra-VanderWeele said.

Two participants discontinued because of increased agitation or aggression, and another five discontinued for other reasons, so 25 children and adolescents aged 6 years to 17 years completed the 8-week study. All participants met DSM-IV and Autism Diagnostic Interview (ADI-R) for autism spectrum disorder.

A double-blind, placebo-controlled study with up to 150 people is underway to confirm these results, Dr. Veenstra-VanderWeele said. When the Food and Drug Administration might approve arbaclofen for treatment of ASD is difficult to determine, he added. "The study initiating now will probably take about 6 months. Then I would anticipate there would be one more follow-up study if that study is positive."

"One really positive thing is this agent ... is closely related to a medication that has been available for decades: baclofen," Dr. Veenstra-VanderWeele said. "Because of that, the safety profile is fairly easy to predict, in contrast to a lot of investigational agents where you really have no idea going in."

Seaside Therapeutics funded the study. Dr. Veenstra-VanderWeele said he receives research funding from Seaside Therapeutics, Novartis, and Roche Pharmaceuticals.

BOCA RATON, FLA. – Social withdrawal and irritability significantly improved when children with autism spectrum disorder took arbaclofen, a new medication in development, according to an open label, multicenter study.

Boosted by promising results with arbaclofen in fragile X syndrome – the leading known cause of inherited autism spectrum disorder (ASD) – Dr. Jeremy M. Veenstra-VanderWeele and his associates launched a study with 32 children and adolescents.

This is the first step to determine whether the GABA-B agonist would help people with ASD who do not have fragile X syndrome, Dr. Veenstra-VanderWeele said in an interview at the annual meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

Children showed significant improvement on the Aberrant Behavior Checklist social withdrawal subscale, from a mean 18.1 at baseline to 12.6 after 8 weeks, based on an intent-to-treat analysis. In addition, the researchers rated more than half – 20 of the 32 kids – as "much improved" or "very much improved" on the Clinical Global Impression for Improvement measure.

At the same time, mean scores on the Aberrant Behavior Checklist Irritability subscale significantly improved from 24.7 to 17.3.

"We saw a lot of promising improvements in people who were taking the medicine," said Dr. Veenstra-VanderWeele, assistant professor in psychiatry at Vanderbilt University in Nashville.

"We did see some adverse events, as you would expect. None of these were terribly severe, and most of them looked similar to fluctuations in peoples’ baseline behavior," Dr. Veenstra-VanderWeele said. One severe adverse event was increased aggression during a planned taper of arbaclofen.

"The medicine was very well tolerated, especially in contrast to available medicines in autism, which, unfortunately, can have significant side effects," Dr. Veenstra-VanderWeele said.

Two participants discontinued because of increased agitation or aggression, and another five discontinued for other reasons, so 25 children and adolescents aged 6 years to 17 years completed the 8-week study. All participants met DSM-IV and Autism Diagnostic Interview (ADI-R) for autism spectrum disorder.

A double-blind, placebo-controlled study with up to 150 people is underway to confirm these results, Dr. Veenstra-VanderWeele said. When the Food and Drug Administration might approve arbaclofen for treatment of ASD is difficult to determine, he added. "The study initiating now will probably take about 6 months. Then I would anticipate there would be one more follow-up study if that study is positive."

"One really positive thing is this agent ... is closely related to a medication that has been available for decades: baclofen," Dr. Veenstra-VanderWeele said. "Because of that, the safety profile is fairly easy to predict, in contrast to a lot of investigational agents where you really have no idea going in."

Seaside Therapeutics funded the study. Dr. Veenstra-VanderWeele said he receives research funding from Seaside Therapeutics, Novartis, and Roche Pharmaceuticals.

BOCA RATON, FLA. – Social withdrawal and irritability significantly improved when children with autism spectrum disorder took arbaclofen, a new medication in development, according to an open label, multicenter study.

Boosted by promising results with arbaclofen in fragile X syndrome – the leading known cause of inherited autism spectrum disorder (ASD) – Dr. Jeremy M. Veenstra-VanderWeele and his associates launched a study with 32 children and adolescents.

This is the first step to determine whether the GABA-B agonist would help people with ASD who do not have fragile X syndrome, Dr. Veenstra-VanderWeele said in an interview at the annual meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

Children showed significant improvement on the Aberrant Behavior Checklist social withdrawal subscale, from a mean 18.1 at baseline to 12.6 after 8 weeks, based on an intent-to-treat analysis. In addition, the researchers rated more than half – 20 of the 32 kids – as "much improved" or "very much improved" on the Clinical Global Impression for Improvement measure.

At the same time, mean scores on the Aberrant Behavior Checklist Irritability subscale significantly improved from 24.7 to 17.3.

"We saw a lot of promising improvements in people who were taking the medicine," said Dr. Veenstra-VanderWeele, assistant professor in psychiatry at Vanderbilt University in Nashville.

"We did see some adverse events, as you would expect. None of these were terribly severe, and most of them looked similar to fluctuations in peoples’ baseline behavior," Dr. Veenstra-VanderWeele said. One severe adverse event was increased aggression during a planned taper of arbaclofen.

"The medicine was very well tolerated, especially in contrast to available medicines in autism, which, unfortunately, can have significant side effects," Dr. Veenstra-VanderWeele said.

Two participants discontinued because of increased agitation or aggression, and another five discontinued for other reasons, so 25 children and adolescents aged 6 years to 17 years completed the 8-week study. All participants met DSM-IV and Autism Diagnostic Interview (ADI-R) for autism spectrum disorder.

A double-blind, placebo-controlled study with up to 150 people is underway to confirm these results, Dr. Veenstra-VanderWeele said. When the Food and Drug Administration might approve arbaclofen for treatment of ASD is difficult to determine, he added. "The study initiating now will probably take about 6 months. Then I would anticipate there would be one more follow-up study if that study is positive."

"One really positive thing is this agent ... is closely related to a medication that has been available for decades: baclofen," Dr. Veenstra-VanderWeele said. "Because of that, the safety profile is fairly easy to predict, in contrast to a lot of investigational agents where you really have no idea going in."

Seaside Therapeutics funded the study. Dr. Veenstra-VanderWeele said he receives research funding from Seaside Therapeutics, Novartis, and Roche Pharmaceuticals.

BOCA RATON, FLA.  – Patients with major depressive disorder who provided their primary care physician with monthly ratings of their symptoms were more likely to respond to antidepressant treatment and to achieve remission compared with a usual care group, findings of a prospective, observational cohort study have shown.

In a multivariate analysis that controlled for significant differences in baseline characteristics, patients who provided monthly updates were twice as likely to respond to therapy (odds ratio, 2.02) and 59% more likely to achieve remission (OR, 1.59) compared with the usual care group.

A total of 83 primary care physicians enrolled 915 patients with major depressive disorder in the Clinical Outcomes in Measurement-Based Treatment (COMET) trial. Physicians were alternatively assigned to an intervention group that received monthly patient symptom ratings on the 9-item Patient Health Questionnaire (PHQ-9) or a usual care group, with PHQ-9 feedback only at the 6-month study end. A total of 380 patients in the intervention group and 284 in the usual care group completed all measures and were assessed further.

Usual care may be insufficient to monitor patient response to antidepressant treatment in the primary care setting, Dr. Trina Chang said at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

"We found there is not a lot of change going on in this first 6 months in these patients with major depression," Dr. Chang said in an interview. For example, 43% of 253 patients who received usual care had no treatment changes during the study.

"There are a couple of different ways to interpret it. The wishful thinking way ... would be [that] all our patients got better so they didn’t need treatment changes," said Dr. Chang, a psychiatrist at Massachusetts General Hospital and Harvard Medical School in Boston.

"Unfortunately, because the study also found [that] less than half of patients go into remission, probably more of them should have been having changes" to their treatment regimen.

In the usual care group, 58% scored 5 or higher on the PHQ-9 at 6 months and were considered nonremitters.

In a subset of the usual care group that had 6-month PHQ-9 scores, among participants who had less than a 25% improvement at that time compared with baseline, only 15% had a treatment change during the study. The findings "indicate an area where there could be a lot of improvement," she said. If the remaining 85% of patients were to get treatment adjustments, "we could do a lot to improve depression outcomes."

None of the participants had received treatment within 120 days prior to enrollment. The primary care physicians were free to choose any kind of antidepressant therapy. Most patients started monotherapy that included selective serotonin reuptake inhibitors for 63%, selective norepinephrine reuptake inhibitors for 25%, or bupropion for 10%. Only 0.4% of patients received an initial augmentation treatment.

Of the patients who received a change in treatment, 17% switched antidepressants; 16% had a dose titration of their initial medication (up or down); 5% had another type of medication added (for example, a benzodiazepine); 3% received augmentation with an antipsychotic, stimulant, or antiepileptic; and 2% received a second antidepressant. The remaining 57% of patients discontinued treatment.

Mean age was 47 years in the intervention group and 45 years in the usual care patients. Women made up 64% of the intervention group and 67% of the usual care group. There were some baseline differences between groups, including a significantly greater proportion of intervention group patients who had Medicaid insurance, were unemployed, and were black or African American. In contrast, the usual care group had a significantly greater proportion of participants who were employed full time, had a 4-year college degree, were married, and were white, Hispanic, or Latino.

Remission was achieved in 48% of the intervention group versus 43% of the usual care group. Complete response rates were achieved in 67% and 60% of the groups, respectively. At 6 months, partial responses were noted in 16% of the intervention and 18% of the usual care groups.

Potential solutions can involve both providers and patients, Dr. Chang said. "On the provider end, anything that could help them detect symptoms and follow up on patients better ... would help." In addition, symptom reporting coupled with treatment algorithms and/or a collaborative care model with a care manager who could more frequently and closely monitor patient treatment response could help, she said.

"On the patient end, anything that might help them to not discontinue their medications would help," she added. Making patients feel supported and answering their questions could all bolster compliance with treatment and possibly improve outcomes.

Dr. Chang said she has received research funding from AstraZeneca, CeNeRx, Euthymics, Forest Laboratories, GlaxoSmithKline, Johnson & Johnson, and Pfizer. Some of the COMET study coauthors are employees of Bristol-Myers Squibb.

BOCA RATON, FLA.  – Patients with major depressive disorder who provided their primary care physician with monthly ratings of their symptoms were more likely to respond to antidepressant treatment and to achieve remission compared with a usual care group, findings of a prospective, observational cohort study have shown.

In a multivariate analysis that controlled for significant differences in baseline characteristics, patients who provided monthly updates were twice as likely to respond to therapy (odds ratio, 2.02) and 59% more likely to achieve remission (OR, 1.59) compared with the usual care group.

A total of 83 primary care physicians enrolled 915 patients with major depressive disorder in the Clinical Outcomes in Measurement-Based Treatment (COMET) trial. Physicians were alternatively assigned to an intervention group that received monthly patient symptom ratings on the 9-item Patient Health Questionnaire (PHQ-9) or a usual care group, with PHQ-9 feedback only at the 6-month study end. A total of 380 patients in the intervention group and 284 in the usual care group completed all measures and were assessed further.

Usual care may be insufficient to monitor patient response to antidepressant treatment in the primary care setting, Dr. Trina Chang said at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

"We found there is not a lot of change going on in this first 6 months in these patients with major depression," Dr. Chang said in an interview. For example, 43% of 253 patients who received usual care had no treatment changes during the study.

"There are a couple of different ways to interpret it. The wishful thinking way ... would be [that] all our patients got better so they didn’t need treatment changes," said Dr. Chang, a psychiatrist at Massachusetts General Hospital and Harvard Medical School in Boston.

"Unfortunately, because the study also found [that] less than half of patients go into remission, probably more of them should have been having changes" to their treatment regimen.

In the usual care group, 58% scored 5 or higher on the PHQ-9 at 6 months and were considered nonremitters.

In a subset of the usual care group that had 6-month PHQ-9 scores, among participants who had less than a 25% improvement at that time compared with baseline, only 15% had a treatment change during the study. The findings "indicate an area where there could be a lot of improvement," she said. If the remaining 85% of patients were to get treatment adjustments, "we could do a lot to improve depression outcomes."

None of the participants had received treatment within 120 days prior to enrollment. The primary care physicians were free to choose any kind of antidepressant therapy. Most patients started monotherapy that included selective serotonin reuptake inhibitors for 63%, selective norepinephrine reuptake inhibitors for 25%, or bupropion for 10%. Only 0.4% of patients received an initial augmentation treatment.

Of the patients who received a change in treatment, 17% switched antidepressants; 16% had a dose titration of their initial medication (up or down); 5% had another type of medication added (for example, a benzodiazepine); 3% received augmentation with an antipsychotic, stimulant, or antiepileptic; and 2% received a second antidepressant. The remaining 57% of patients discontinued treatment.

Mean age was 47 years in the intervention group and 45 years in the usual care patients. Women made up 64% of the intervention group and 67% of the usual care group. There were some baseline differences between groups, including a significantly greater proportion of intervention group patients who had Medicaid insurance, were unemployed, and were black or African American. In contrast, the usual care group had a significantly greater proportion of participants who were employed full time, had a 4-year college degree, were married, and were white, Hispanic, or Latino.

Remission was achieved in 48% of the intervention group versus 43% of the usual care group. Complete response rates were achieved in 67% and 60% of the groups, respectively. At 6 months, partial responses were noted in 16% of the intervention and 18% of the usual care groups.

Potential solutions can involve both providers and patients, Dr. Chang said. "On the provider end, anything that could help them detect symptoms and follow up on patients better ... would help." In addition, symptom reporting coupled with treatment algorithms and/or a collaborative care model with a care manager who could more frequently and closely monitor patient treatment response could help, she said.

"On the patient end, anything that might help them to not discontinue their medications would help," she added. Making patients feel supported and answering their questions could all bolster compliance with treatment and possibly improve outcomes.

Dr. Chang said she has received research funding from AstraZeneca, CeNeRx, Euthymics, Forest Laboratories, GlaxoSmithKline, Johnson & Johnson, and Pfizer. Some of the COMET study coauthors are employees of Bristol-Myers Squibb.

BOCA RATON, FLA.  – Patients with major depressive disorder who provided their primary care physician with monthly ratings of their symptoms were more likely to respond to antidepressant treatment and to achieve remission compared with a usual care group, findings of a prospective, observational cohort study have shown.

In a multivariate analysis that controlled for significant differences in baseline characteristics, patients who provided monthly updates were twice as likely to respond to therapy (odds ratio, 2.02) and 59% more likely to achieve remission (OR, 1.59) compared with the usual care group.

A total of 83 primary care physicians enrolled 915 patients with major depressive disorder in the Clinical Outcomes in Measurement-Based Treatment (COMET) trial. Physicians were alternatively assigned to an intervention group that received monthly patient symptom ratings on the 9-item Patient Health Questionnaire (PHQ-9) or a usual care group, with PHQ-9 feedback only at the 6-month study end. A total of 380 patients in the intervention group and 284 in the usual care group completed all measures and were assessed further.

Usual care may be insufficient to monitor patient response to antidepressant treatment in the primary care setting, Dr. Trina Chang said at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

"We found there is not a lot of change going on in this first 6 months in these patients with major depression," Dr. Chang said in an interview. For example, 43% of 253 patients who received usual care had no treatment changes during the study.

"There are a couple of different ways to interpret it. The wishful thinking way ... would be [that] all our patients got better so they didn’t need treatment changes," said Dr. Chang, a psychiatrist at Massachusetts General Hospital and Harvard Medical School in Boston.

"Unfortunately, because the study also found [that] less than half of patients go into remission, probably more of them should have been having changes" to their treatment regimen.

In the usual care group, 58% scored 5 or higher on the PHQ-9 at 6 months and were considered nonremitters.

In a subset of the usual care group that had 6-month PHQ-9 scores, among participants who had less than a 25% improvement at that time compared with baseline, only 15% had a treatment change during the study. The findings "indicate an area where there could be a lot of improvement," she said. If the remaining 85% of patients were to get treatment adjustments, "we could do a lot to improve depression outcomes."

None of the participants had received treatment within 120 days prior to enrollment. The primary care physicians were free to choose any kind of antidepressant therapy. Most patients started monotherapy that included selective serotonin reuptake inhibitors for 63%, selective norepinephrine reuptake inhibitors for 25%, or bupropion for 10%. Only 0.4% of patients received an initial augmentation treatment.

Of the patients who received a change in treatment, 17% switched antidepressants; 16% had a dose titration of their initial medication (up or down); 5% had another type of medication added (for example, a benzodiazepine); 3% received augmentation with an antipsychotic, stimulant, or antiepileptic; and 2% received a second antidepressant. The remaining 57% of patients discontinued treatment.

Mean age was 47 years in the intervention group and 45 years in the usual care patients. Women made up 64% of the intervention group and 67% of the usual care group. There were some baseline differences between groups, including a significantly greater proportion of intervention group patients who had Medicaid insurance, were unemployed, and were black or African American. In contrast, the usual care group had a significantly greater proportion of participants who were employed full time, had a 4-year college degree, were married, and were white, Hispanic, or Latino.

Remission was achieved in 48% of the intervention group versus 43% of the usual care group. Complete response rates were achieved in 67% and 60% of the groups, respectively. At 6 months, partial responses were noted in 16% of the intervention and 18% of the usual care groups.

Potential solutions can involve both providers and patients, Dr. Chang said. "On the provider end, anything that could help them detect symptoms and follow up on patients better ... would help." In addition, symptom reporting coupled with treatment algorithms and/or a collaborative care model with a care manager who could more frequently and closely monitor patient treatment response could help, she said.

"On the patient end, anything that might help them to not discontinue their medications would help," she added. Making patients feel supported and answering their questions could all bolster compliance with treatment and possibly improve outcomes.

Dr. Chang said she has received research funding from AstraZeneca, CeNeRx, Euthymics, Forest Laboratories, GlaxoSmithKline, Johnson & Johnson, and Pfizer. Some of the COMET study coauthors are employees of Bristol-Myers Squibb.

BOCA RATON, FLA.  – Proposed changes for the diagnosis of patients with mixed depressive episodes for the next edition of the Diagnostic and Statistical Manual of Mental Disorders will more closely reflect the patients psychiatrists see in their everyday practice, Ellen Frank, Ph.D., said.

The current DSM-IV-TR definition of a mixed episode requires that a patient meet full criteria for a manic episode and full criteria for a major depressive episode (except for duration) nearly every day for at least a 1-week period. "What did I think was wrong with this definition? As far as I’m concerned, these patients don’t exist," Dr. Frank said at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

I would argue that if you really carefully distinguish, for example, agitation from increased goal-directed activity, [and] if you really carefully distinguish the potential overlapping symptoms, these patients are about as rare as unicorns," Dr. Frank said.

"We thought the current criteria too restrictive, and they are rarely adhered to. When we say the patient is mixed, we rarely mean that the patient meets full criteria for both poles," said Dr. Frank, professor of psychiatry and psychology at the University of Pittsburgh. "This results in a lot of confusion, a lack of precision, and fails to identify [those] who are at risk of progression from unipolar to bipolar disorder."

Inappropriate treatment selection is another possibility with the DSM-IV-TR definition, said Dr. Frank, director of the Depression and Manic Depression Prevention Program at the Western Psychiatric Institute and Clinic in Pittsburgh, and a member of the DSM-5 Mood Disorders Work Group. In addition, "the consequence of the current definition in common use is that we underestimate suicide risk, because I do believe these patients are at excessive risk of suicide.

"This is a horrible state to be in, and we need to figure out how to do a better job of treating it."

What Dr. Frank and her collaborators on the working group propose for the DSM-5 is a mixed specifier that indicates the presence of symptoms – not the syndrome – of the opposite pole. The specifier would be applied to both episodes of mania and depression, and would be applicable in the context of both unipolar and bipolar lifetime diagnoses.

The psychiatric history of those who experience mixed states tend to include early onset of illness, multiple previous episodes, suicidal behavior, substance abuse, and other comorbid diagnoses that tend to be associated with bipolar disorder (such as panic).

Under the proposed construct, if a "mixed" patient is predominantly depressed, they meet full criteria for a major depressive episode and have at least three of the following nearly every day during the episode:

• Elevated mood.

• Decreased need for sleep (not insomnia).

• Goal-directed activity.

• Increased energy or visible hyperactivity (again, goal directed).

• Grandiosity.

• Accelerated speech.

• Racing thoughts.

If the patient is predominantly manic or hypomanic, they meet full criteria for the manic or hypomanic episode and feature at least three of the following:

• Subjective depression.

• Worry.

• Self-reproach or guilt.

• Negative evaluation of self.

• Hopelessness.

• Suicidal ideation or behavior.

• Anhedonia.

• Fatigue.

• Psychomotor retardation.

Interestingly, the proposed criteria do not include what the working group considered to be characteristics of both poles: irritability, indecisiveness, and psychomotor agitation (which is distinguished from goal-directed activity). In addition, the proposal does not include distractibility, "which I’ve come to believe is actually a feature of almost every patient anywhere on the bipolar spectrum," Dr. Frank said.

Insomnia or hypersomnia is another shared symptom not included in the specifier. Insomnia "is difficult to distinguish as a manic or depressive symptom," said Dr. Roy H. Perlis, director of the bipolar research program at Massachusetts General Hospital and instructor in psychiatry at Harvard Medical School, both in Boston.

Family aggregation, psychiatric history, concurrent psychiatric symptoms, and, particularly, treatment outcome were used as validators for the proposed specifier, Dr. Frank said. For example, in terms of treatment outcome, she added that a poor response to lithium and hypomanic symptoms during predominantly depressive states are associated with destabilization on antidepressants.

DSM-5 field trials are underway to assess the proposed criteria. The goal is to test the clinical acceptability and utility of the new constructs in both academic and practice settings. In addition, the reliability of diagnosis will be assessed in the academic component of the field trials. The clinics testing the mixed depression specifier include the Mayo Clinic, Rochester, Minn.; University of California,Los Angeles; the University of Texas Health Science Center at San Antonio; and the Veterans Affairs Medical Centers in Dallas and Houston.

Dr. Frank’s disclosures include Guilford Press and Servier International. Dr. Perlis’s disclosures include Concordant Rater Systems, Proteus Biomedical, and RIDVentures.

BOCA RATON, FLA.  – Proposed changes for the diagnosis of patients with mixed depressive episodes for the next edition of the Diagnostic and Statistical Manual of Mental Disorders will more closely reflect the patients psychiatrists see in their everyday practice, Ellen Frank, Ph.D., said.

The current DSM-IV-TR definition of a mixed episode requires that a patient meet full criteria for a manic episode and full criteria for a major depressive episode (except for duration) nearly every day for at least a 1-week period. "What did I think was wrong with this definition? As far as I’m concerned, these patients don’t exist," Dr. Frank said at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

I would argue that if you really carefully distinguish, for example, agitation from increased goal-directed activity, [and] if you really carefully distinguish the potential overlapping symptoms, these patients are about as rare as unicorns," Dr. Frank said.

"We thought the current criteria too restrictive, and they are rarely adhered to. When we say the patient is mixed, we rarely mean that the patient meets full criteria for both poles," said Dr. Frank, professor of psychiatry and psychology at the University of Pittsburgh. "This results in a lot of confusion, a lack of precision, and fails to identify [those] who are at risk of progression from unipolar to bipolar disorder."

Inappropriate treatment selection is another possibility with the DSM-IV-TR definition, said Dr. Frank, director of the Depression and Manic Depression Prevention Program at the Western Psychiatric Institute and Clinic in Pittsburgh, and a member of the DSM-5 Mood Disorders Work Group. In addition, "the consequence of the current definition in common use is that we underestimate suicide risk, because I do believe these patients are at excessive risk of suicide.

"This is a horrible state to be in, and we need to figure out how to do a better job of treating it."

What Dr. Frank and her collaborators on the working group propose for the DSM-5 is a mixed specifier that indicates the presence of symptoms – not the syndrome – of the opposite pole. The specifier would be applied to both episodes of mania and depression, and would be applicable in the context of both unipolar and bipolar lifetime diagnoses.

The psychiatric history of those who experience mixed states tend to include early onset of illness, multiple previous episodes, suicidal behavior, substance abuse, and other comorbid diagnoses that tend to be associated with bipolar disorder (such as panic).

Under the proposed construct, if a "mixed" patient is predominantly depressed, they meet full criteria for a major depressive episode and have at least three of the following nearly every day during the episode:

• Elevated mood.

• Decreased need for sleep (not insomnia).

• Goal-directed activity.

• Increased energy or visible hyperactivity (again, goal directed).

• Grandiosity.

• Accelerated speech.

• Racing thoughts.

If the patient is predominantly manic or hypomanic, they meet full criteria for the manic or hypomanic episode and feature at least three of the following:

• Subjective depression.

• Worry.

• Self-reproach or guilt.

• Negative evaluation of self.

• Hopelessness.

• Suicidal ideation or behavior.

• Anhedonia.

• Fatigue.

• Psychomotor retardation.

Interestingly, the proposed criteria do not include what the working group considered to be characteristics of both poles: irritability, indecisiveness, and psychomotor agitation (which is distinguished from goal-directed activity). In addition, the proposal does not include distractibility, "which I’ve come to believe is actually a feature of almost every patient anywhere on the bipolar spectrum," Dr. Frank said.

Insomnia or hypersomnia is another shared symptom not included in the specifier. Insomnia "is difficult to distinguish as a manic or depressive symptom," said Dr. Roy H. Perlis, director of the bipolar research program at Massachusetts General Hospital and instructor in psychiatry at Harvard Medical School, both in Boston.

Family aggregation, psychiatric history, concurrent psychiatric symptoms, and, particularly, treatment outcome were used as validators for the proposed specifier, Dr. Frank said. For example, in terms of treatment outcome, she added that a poor response to lithium and hypomanic symptoms during predominantly depressive states are associated with destabilization on antidepressants.

DSM-5 field trials are underway to assess the proposed criteria. The goal is to test the clinical acceptability and utility of the new constructs in both academic and practice settings. In addition, the reliability of diagnosis will be assessed in the academic component of the field trials. The clinics testing the mixed depression specifier include the Mayo Clinic, Rochester, Minn.; University of California,Los Angeles; the University of Texas Health Science Center at San Antonio; and the Veterans Affairs Medical Centers in Dallas and Houston.

Dr. Frank’s disclosures include Guilford Press and Servier International. Dr. Perlis’s disclosures include Concordant Rater Systems, Proteus Biomedical, and RIDVentures.

BOCA RATON, FLA.  – Proposed changes for the diagnosis of patients with mixed depressive episodes for the next edition of the Diagnostic and Statistical Manual of Mental Disorders will more closely reflect the patients psychiatrists see in their everyday practice, Ellen Frank, Ph.D., said.

The current DSM-IV-TR definition of a mixed episode requires that a patient meet full criteria for a manic episode and full criteria for a major depressive episode (except for duration) nearly every day for at least a 1-week period. "What did I think was wrong with this definition? As far as I’m concerned, these patients don’t exist," Dr. Frank said at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

I would argue that if you really carefully distinguish, for example, agitation from increased goal-directed activity, [and] if you really carefully distinguish the potential overlapping symptoms, these patients are about as rare as unicorns," Dr. Frank said.

"We thought the current criteria too restrictive, and they are rarely adhered to. When we say the patient is mixed, we rarely mean that the patient meets full criteria for both poles," said Dr. Frank, professor of psychiatry and psychology at the University of Pittsburgh. "This results in a lot of confusion, a lack of precision, and fails to identify [those] who are at risk of progression from unipolar to bipolar disorder."

Inappropriate treatment selection is another possibility with the DSM-IV-TR definition, said Dr. Frank, director of the Depression and Manic Depression Prevention Program at the Western Psychiatric Institute and Clinic in Pittsburgh, and a member of the DSM-5 Mood Disorders Work Group. In addition, "the consequence of the current definition in common use is that we underestimate suicide risk, because I do believe these patients are at excessive risk of suicide.

"This is a horrible state to be in, and we need to figure out how to do a better job of treating it."

What Dr. Frank and her collaborators on the working group propose for the DSM-5 is a mixed specifier that indicates the presence of symptoms – not the syndrome – of the opposite pole. The specifier would be applied to both episodes of mania and depression, and would be applicable in the context of both unipolar and bipolar lifetime diagnoses.

The psychiatric history of those who experience mixed states tend to include early onset of illness, multiple previous episodes, suicidal behavior, substance abuse, and other comorbid diagnoses that tend to be associated with bipolar disorder (such as panic).

Under the proposed construct, if a "mixed" patient is predominantly depressed, they meet full criteria for a major depressive episode and have at least three of the following nearly every day during the episode:

• Elevated mood.

• Decreased need for sleep (not insomnia).

• Goal-directed activity.

• Increased energy or visible hyperactivity (again, goal directed).

• Grandiosity.

• Accelerated speech.

• Racing thoughts.

If the patient is predominantly manic or hypomanic, they meet full criteria for the manic or hypomanic episode and feature at least three of the following:

• Subjective depression.

• Worry.

• Self-reproach or guilt.

• Negative evaluation of self.

• Hopelessness.

• Suicidal ideation or behavior.

• Anhedonia.

• Fatigue.

• Psychomotor retardation.

Interestingly, the proposed criteria do not include what the working group considered to be characteristics of both poles: irritability, indecisiveness, and psychomotor agitation (which is distinguished from goal-directed activity). In addition, the proposal does not include distractibility, "which I’ve come to believe is actually a feature of almost every patient anywhere on the bipolar spectrum," Dr. Frank said.

Insomnia or hypersomnia is another shared symptom not included in the specifier. Insomnia "is difficult to distinguish as a manic or depressive symptom," said Dr. Roy H. Perlis, director of the bipolar research program at Massachusetts General Hospital and instructor in psychiatry at Harvard Medical School, both in Boston.

Family aggregation, psychiatric history, concurrent psychiatric symptoms, and, particularly, treatment outcome were used as validators for the proposed specifier, Dr. Frank said. For example, in terms of treatment outcome, she added that a poor response to lithium and hypomanic symptoms during predominantly depressive states are associated with destabilization on antidepressants.

DSM-5 field trials are underway to assess the proposed criteria. The goal is to test the clinical acceptability and utility of the new constructs in both academic and practice settings. In addition, the reliability of diagnosis will be assessed in the academic component of the field trials. The clinics testing the mixed depression specifier include the Mayo Clinic, Rochester, Minn.; University of California,Los Angeles; the University of Texas Health Science Center at San Antonio; and the Veterans Affairs Medical Centers in Dallas and Houston.

Dr. Frank’s disclosures include Guilford Press and Servier International. Dr. Perlis’s disclosures include Concordant Rater Systems, Proteus Biomedical, and RIDVentures.

BOCA RATON, FLA.  – Proposed changes for the diagnosis of patients with mixed depressive episodes for the next edition of the Diagnostic and Statistical Manual of Mental Disorders will more closely reflect the patients psychiatrists see in their everyday practice, Ellen Frank, Ph.D., said.

The current DSM-IV-TR definition of a mixed episode requires that a patient meet full criteria for a manic episode and full criteria for a major depressive episode (except for duration) nearly every day for at least a 1-week period. "What did I think was wrong with this definition? As far as I’m concerned, these patients don’t exist," Dr. Frank said at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

I would argue that if you really carefully distinguish, for example, agitation from increased goal-directed activity, [and] if you really carefully distinguish the potential overlapping symptoms, these patients are about as rare as unicorns," Dr. Frank said.

"We thought the current criteria too restrictive, and they are rarely adhered to. When we say the patient is mixed, we rarely mean that the patient meets full criteria for both poles," said Dr. Frank, professor of psychiatry and psychology at the University of Pittsburgh. "This results in a lot of confusion, a lack of precision, and fails to identify [those] who are at risk of progression from unipolar to bipolar disorder."

Inappropriate treatment selection is another possibility with the DSM-IV-TR definition, said Dr. Frank, director of the Depression and Manic Depression Prevention Program at the Western Psychiatric Institute and Clinic in Pittsburgh, and a member of the DSM-5 Mood Disorders Work Group. In addition, "the consequence of the current definition in common use is that we underestimate suicide risk, because I do believe these patients are at excessive risk of suicide.

"This is a horrible state to be in, and we need to figure out how to do a better job of treating it."

What Dr. Frank and her collaborators on the working group propose for the DSM-5 is a mixed specifier that indicates the presence of symptoms – not the syndrome – of the opposite pole. The specifier would be applied to both episodes of mania and depression, and would be applicable in the context of both unipolar and bipolar lifetime diagnoses.

The psychiatric history of those who experience mixed states tend to include early onset of illness, multiple previous episodes, suicidal behavior, substance abuse, and other comorbid diagnoses that tend to be associated with bipolar disorder (such as panic).

Under the proposed construct, if a "mixed" patient is predominantly depressed, they meet full criteria for a major depressive episode and have at least three of the following nearly every day during the episode:

• Elevated mood.

• Decreased need for sleep (not insomnia).

• Goal-directed activity.

• Increased energy or visible hyperactivity (again, goal directed).

• Grandiosity.

• Accelerated speech.

• Racing thoughts.

If the patient is predominantly manic or hypomanic, they meet full criteria for the manic or hypomanic episode and feature at least three of the following:

• Subjective depression.

• Worry.

• Self-reproach or guilt.

• Negative evaluation of self.

• Hopelessness.

• Suicidal ideation or behavior.

• Anhedonia.

• Fatigue.

• Psychomotor retardation.

Interestingly, the proposed criteria do not include what the working group considered to be characteristics of both poles: irritability, indecisiveness, and psychomotor agitation (which is distinguished from goal-directed activity). In addition, the proposal does not include distractibility, "which I’ve come to believe is actually a feature of almost every patient anywhere on the bipolar spectrum," Dr. Frank said.

Insomnia or hypersomnia is another shared symptom not included in the specifier. Insomnia "is difficult to distinguish as a manic or depressive symptom," said Dr. Roy H. Perlis, director of the bipolar research program at Massachusetts General Hospital and instructor in psychiatry at Harvard Medical School, both in Boston.

Family aggregation, psychiatric history, concurrent psychiatric symptoms, and, particularly, treatment outcome were used as validators for the proposed specifier, Dr. Frank said. For example, in terms of treatment outcome, she added that a poor response to lithium and hypomanic symptoms during predominantly depressive states are associated with destabilization on antidepressants.

DSM-5 field trials are underway to assess the proposed criteria. The goal is to test the clinical acceptability and utility of the new constructs in both academic and practice settings. In addition, the reliability of diagnosis will be assessed in the academic component of the field trials. The clinics testing the mixed depression specifier include the Mayo Clinic, Rochester, Minn.; University of California,Los Angeles; the University of Texas Health Science Center at San Antonio; and the Veterans Affairs Medical Centers in Dallas and Houston.

Dr. Frank’s disclosures include Guilford Press and Servier International. Dr. Perlis’s disclosures include Concordant Rater Systems, Proteus Biomedical, and RIDVentures.

BOCA RATON, FLA.  – Proposed changes for the diagnosis of patients with mixed depressive episodes for the next edition of the Diagnostic and Statistical Manual of Mental Disorders will more closely reflect the patients psychiatrists see in their everyday practice, Ellen Frank, Ph.D., said.

The current DSM-IV-TR definition of a mixed episode requires that a patient meet full criteria for a manic episode and full criteria for a major depressive episode (except for duration) nearly every day for at least a 1-week period. "What did I think was wrong with this definition? As far as I’m concerned, these patients don’t exist," Dr. Frank said at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

I would argue that if you really carefully distinguish, for example, agitation from increased goal-directed activity, [and] if you really carefully distinguish the potential overlapping symptoms, these patients are about as rare as unicorns," Dr. Frank said.

"We thought the current criteria too restrictive, and they are rarely adhered to. When we say the patient is mixed, we rarely mean that the patient meets full criteria for both poles," said Dr. Frank, professor of psychiatry and psychology at the University of Pittsburgh. "This results in a lot of confusion, a lack of precision, and fails to identify [those] who are at risk of progression from unipolar to bipolar disorder."

Inappropriate treatment selection is another possibility with the DSM-IV-TR definition, said Dr. Frank, director of the Depression and Manic Depression Prevention Program at the Western Psychiatric Institute and Clinic in Pittsburgh, and a member of the DSM-5 Mood Disorders Work Group. In addition, "the consequence of the current definition in common use is that we underestimate suicide risk, because I do believe these patients are at excessive risk of suicide.

"This is a horrible state to be in, and we need to figure out how to do a better job of treating it."

What Dr. Frank and her collaborators on the working group propose for the DSM-5 is a mixed specifier that indicates the presence of symptoms – not the syndrome – of the opposite pole. The specifier would be applied to both episodes of mania and depression, and would be applicable in the context of both unipolar and bipolar lifetime diagnoses.

The psychiatric history of those who experience mixed states tend to include early onset of illness, multiple previous episodes, suicidal behavior, substance abuse, and other comorbid diagnoses that tend to be associated with bipolar disorder (such as panic).

Under the proposed construct, if a "mixed" patient is predominantly depressed, they meet full criteria for a major depressive episode and have at least three of the following nearly every day during the episode:

• Elevated mood.

• Decreased need for sleep (not insomnia).

• Goal-directed activity.

• Increased energy or visible hyperactivity (again, goal directed).

• Grandiosity.

• Accelerated speech.

• Racing thoughts.

If the patient is predominantly manic or hypomanic, they meet full criteria for the manic or hypomanic episode and feature at least three of the following:

• Subjective depression.

• Worry.

• Self-reproach or guilt.

• Negative evaluation of self.

• Hopelessness.

• Suicidal ideation or behavior.

• Anhedonia.

• Fatigue.

• Psychomotor retardation.

Interestingly, the proposed criteria do not include what the working group considered to be characteristics of both poles: irritability, indecisiveness, and psychomotor agitation (which is distinguished from goal-directed activity). In addition, the proposal does not include distractibility, "which I’ve come to believe is actually a feature of almost every patient anywhere on the bipolar spectrum," Dr. Frank said.

Insomnia or hypersomnia is another shared symptom not included in the specifier. Insomnia "is difficult to distinguish as a manic or depressive symptom," said Dr. Roy H. Perlis, director of the bipolar research program at Massachusetts General Hospital and instructor in psychiatry at Harvard Medical School, both in Boston.

Family aggregation, psychiatric history, concurrent psychiatric symptoms, and, particularly, treatment outcome were used as validators for the proposed specifier, Dr. Frank said. For example, in terms of treatment outcome, she added that a poor response to lithium and hypomanic symptoms during predominantly depressive states are associated with destabilization on antidepressants.

DSM-5 field trials are underway to assess the proposed criteria. The goal is to test the clinical acceptability and utility of the new constructs in both academic and practice settings. In addition, the reliability of diagnosis will be assessed in the academic component of the field trials. The clinics testing the mixed depression specifier include the Mayo Clinic, Rochester, Minn.; University of California,Los Angeles; the University of Texas Health Science Center at San Antonio; and the Veterans Affairs Medical Centers in Dallas and Houston.

Dr. Frank’s disclosures include Guilford Press and Servier International. Dr. Perlis’s disclosures include Concordant Rater Systems, Proteus Biomedical, and RIDVentures.

BOCA RATON, FLA.  – Proposed changes for the diagnosis of patients with mixed depressive episodes for the next edition of the Diagnostic and Statistical Manual of Mental Disorders will more closely reflect the patients psychiatrists see in their everyday practice, Ellen Frank, Ph.D., said.

The current DSM-IV-TR definition of a mixed episode requires that a patient meet full criteria for a manic episode and full criteria for a major depressive episode (except for duration) nearly every day for at least a 1-week period. "What did I think was wrong with this definition? As far as I’m concerned, these patients don’t exist," Dr. Frank said at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

I would argue that if you really carefully distinguish, for example, agitation from increased goal-directed activity, [and] if you really carefully distinguish the potential overlapping symptoms, these patients are about as rare as unicorns," Dr. Frank said.

"We thought the current criteria too restrictive, and they are rarely adhered to. When we say the patient is mixed, we rarely mean that the patient meets full criteria for both poles," said Dr. Frank, professor of psychiatry and psychology at the University of Pittsburgh. "This results in a lot of confusion, a lack of precision, and fails to identify [those] who are at risk of progression from unipolar to bipolar disorder."

Inappropriate treatment selection is another possibility with the DSM-IV-TR definition, said Dr. Frank, director of the Depression and Manic Depression Prevention Program at the Western Psychiatric Institute and Clinic in Pittsburgh, and a member of the DSM-5 Mood Disorders Work Group. In addition, "the consequence of the current definition in common use is that we underestimate suicide risk, because I do believe these patients are at excessive risk of suicide.

"This is a horrible state to be in, and we need to figure out how to do a better job of treating it."

What Dr. Frank and her collaborators on the working group propose for the DSM-5 is a mixed specifier that indicates the presence of symptoms – not the syndrome – of the opposite pole. The specifier would be applied to both episodes of mania and depression, and would be applicable in the context of both unipolar and bipolar lifetime diagnoses.

The psychiatric history of those who experience mixed states tend to include early onset of illness, multiple previous episodes, suicidal behavior, substance abuse, and other comorbid diagnoses that tend to be associated with bipolar disorder (such as panic).

Under the proposed construct, if a "mixed" patient is predominantly depressed, they meet full criteria for a major depressive episode and have at least three of the following nearly every day during the episode:

• Elevated mood.

• Decreased need for sleep (not insomnia).

• Goal-directed activity.

• Increased energy or visible hyperactivity (again, goal directed).

• Grandiosity.

• Accelerated speech.

• Racing thoughts.

If the patient is predominantly manic or hypomanic, they meet full criteria for the manic or hypomanic episode and feature at least three of the following:

• Subjective depression.

• Worry.

• Self-reproach or guilt.

• Negative evaluation of self.

• Hopelessness.

• Suicidal ideation or behavior.

• Anhedonia.

• Fatigue.

• Psychomotor retardation.

Interestingly, the proposed criteria do not include what the working group considered to be characteristics of both poles: irritability, indecisiveness, and psychomotor agitation (which is distinguished from goal-directed activity). In addition, the proposal does not include distractibility, "which I’ve come to believe is actually a feature of almost every patient anywhere on the bipolar spectrum," Dr. Frank said.

Insomnia or hypersomnia is another shared symptom not included in the specifier. Insomnia "is difficult to distinguish as a manic or depressive symptom," said Dr. Roy H. Perlis, director of the bipolar research program at Massachusetts General Hospital and instructor in psychiatry at Harvard Medical School, both in Boston.

Family aggregation, psychiatric history, concurrent psychiatric symptoms, and, particularly, treatment outcome were used as validators for the proposed specifier, Dr. Frank said. For example, in terms of treatment outcome, she added that a poor response to lithium and hypomanic symptoms during predominantly depressive states are associated with destabilization on antidepressants.

DSM-5 field trials are underway to assess the proposed criteria. The goal is to test the clinical acceptability and utility of the new constructs in both academic and practice settings. In addition, the reliability of diagnosis will be assessed in the academic component of the field trials. The clinics testing the mixed depression specifier include the Mayo Clinic, Rochester, Minn.; University of California,Los Angeles; the University of Texas Health Science Center at San Antonio; and the Veterans Affairs Medical Centers in Dallas and Houston.

Dr. Frank’s disclosures include Guilford Press and Servier International. Dr. Perlis’s disclosures include Concordant Rater Systems, Proteus Biomedical, and RIDVentures.

BOCA RATON, FLA.  – Proposed changes for the diagnosis of patients with mixed depressive episodes for the next edition of the Diagnostic and Statistical Manual of Mental Disorders will more closely reflect the patients psychiatrists see in their everyday practice, Ellen Frank, Ph.D., said.

The current DSM-IV-TR definition of a mixed episode requires that a patient meet full criteria for a manic episode and full criteria for a major depressive episode (except for duration) nearly every day for at least a 1-week period. "What did I think was wrong with this definition? As far as I’m concerned, these patients don’t exist," Dr. Frank said at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

I would argue that if you really carefully distinguish, for example, agitation from increased goal-directed activity, [and] if you really carefully distinguish the potential overlapping symptoms, these patients are about as rare as unicorns," Dr. Frank said.

"We thought the current criteria too restrictive, and they are rarely adhered to. When we say the patient is mixed, we rarely mean that the patient meets full criteria for both poles," said Dr. Frank, professor of psychiatry and psychology at the University of Pittsburgh. "This results in a lot of confusion, a lack of precision, and fails to identify [those] who are at risk of progression from unipolar to bipolar disorder."

Inappropriate treatment selection is another possibility with the DSM-IV-TR definition, said Dr. Frank, director of the Depression and Manic Depression Prevention Program at the Western Psychiatric Institute and Clinic in Pittsburgh, and a member of the DSM-5 Mood Disorders Work Group. In addition, "the consequence of the current definition in common use is that we underestimate suicide risk, because I do believe these patients are at excessive risk of suicide.

"This is a horrible state to be in, and we need to figure out how to do a better job of treating it."

What Dr. Frank and her collaborators on the working group propose for the DSM-5 is a mixed specifier that indicates the presence of symptoms – not the syndrome – of the opposite pole. The specifier would be applied to both episodes of mania and depression, and would be applicable in the context of both unipolar and bipolar lifetime diagnoses.

The psychiatric history of those who experience mixed states tend to include early onset of illness, multiple previous episodes, suicidal behavior, substance abuse, and other comorbid diagnoses that tend to be associated with bipolar disorder (such as panic).

Under the proposed construct, if a "mixed" patient is predominantly depressed, they meet full criteria for a major depressive episode and have at least three of the following nearly every day during the episode:

• Elevated mood.

• Decreased need for sleep (not insomnia).

• Goal-directed activity.

• Increased energy or visible hyperactivity (again, goal directed).

• Grandiosity.

• Accelerated speech.

• Racing thoughts.

If the patient is predominantly manic or hypomanic, they meet full criteria for the manic or hypomanic episode and feature at least three of the following:

• Subjective depression.

• Worry.

• Self-reproach or guilt.

• Negative evaluation of self.

• Hopelessness.

• Suicidal ideation or behavior.

• Anhedonia.

• Fatigue.

• Psychomotor retardation.

Interestingly, the proposed criteria do not include what the working group considered to be characteristics of both poles: irritability, indecisiveness, and psychomotor agitation (which is distinguished from goal-directed activity). In addition, the proposal does not include distractibility, "which I’ve come to believe is actually a feature of almost every patient anywhere on the bipolar spectrum," Dr. Frank said.

Insomnia or hypersomnia is another shared symptom not included in the specifier. Insomnia "is difficult to distinguish as a manic or depressive symptom," said Dr. Roy H. Perlis, director of the bipolar research program at Massachusetts General Hospital and instructor in psychiatry at Harvard Medical School, both in Boston.

Family aggregation, psychiatric history, concurrent psychiatric symptoms, and, particularly, treatment outcome were used as validators for the proposed specifier, Dr. Frank said. For example, in terms of treatment outcome, she added that a poor response to lithium and hypomanic symptoms during predominantly depressive states are associated with destabilization on antidepressants.

DSM-5 field trials are underway to assess the proposed criteria. The goal is to test the clinical acceptability and utility of the new constructs in both academic and practice settings. In addition, the reliability of diagnosis will be assessed in the academic component of the field trials. The clinics testing the mixed depression specifier include the Mayo Clinic, Rochester, Minn.; University of California,Los Angeles; the University of Texas Health Science Center at San Antonio; and the Veterans Affairs Medical Centers in Dallas and Houston.

Dr. Frank’s disclosures include Guilford Press and Servier International. Dr. Perlis’s disclosures include Concordant Rater Systems, Proteus Biomedical, and RIDVentures.

BOCA RATON, FLA.  – Proposed changes for the diagnosis of patients with mixed depressive episodes for the next edition of the Diagnostic and Statistical Manual of Mental Disorders will more closely reflect the patients psychiatrists see in their everyday practice, Ellen Frank, Ph.D., said.

The current DSM-IV-TR definition of a mixed episode requires that a patient meet full criteria for a manic episode and full criteria for a major depressive episode (except for duration) nearly every day for at least a 1-week period. "What did I think was wrong with this definition? As far as I’m concerned, these patients don’t exist," Dr. Frank said at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

I would argue that if you really carefully distinguish, for example, agitation from increased goal-directed activity, [and] if you really carefully distinguish the potential overlapping symptoms, these patients are about as rare as unicorns," Dr. Frank said.

"We thought the current criteria too restrictive, and they are rarely adhered to. When we say the patient is mixed, we rarely mean that the patient meets full criteria for both poles," said Dr. Frank, professor of psychiatry and psychology at the University of Pittsburgh. "This results in a lot of confusion, a lack of precision, and fails to identify [those] who are at risk of progression from unipolar to bipolar disorder."

Inappropriate treatment selection is another possibility with the DSM-IV-TR definition, said Dr. Frank, director of the Depression and Manic Depression Prevention Program at the Western Psychiatric Institute and Clinic in Pittsburgh, and a member of the DSM-5 Mood Disorders Work Group. In addition, "the consequence of the current definition in common use is that we underestimate suicide risk, because I do believe these patients are at excessive risk of suicide.

"This is a horrible state to be in, and we need to figure out how to do a better job of treating it."

What Dr. Frank and her collaborators on the working group propose for the DSM-5 is a mixed specifier that indicates the presence of symptoms – not the syndrome – of the opposite pole. The specifier would be applied to both episodes of mania and depression, and would be applicable in the context of both unipolar and bipolar lifetime diagnoses.

The psychiatric history of those who experience mixed states tend to include early onset of illness, multiple previous episodes, suicidal behavior, substance abuse, and other comorbid diagnoses that tend to be associated with bipolar disorder (such as panic).

Under the proposed construct, if a "mixed" patient is predominantly depressed, they meet full criteria for a major depressive episode and have at least three of the following nearly every day during the episode:

• Elevated mood.

• Decreased need for sleep (not insomnia).

• Goal-directed activity.

• Increased energy or visible hyperactivity (again, goal directed).

• Grandiosity.

• Accelerated speech.

• Racing thoughts.

If the patient is predominantly manic or hypomanic, they meet full criteria for the manic or hypomanic episode and feature at least three of the following:

• Subjective depression.

• Worry.

• Self-reproach or guilt.

• Negative evaluation of self.

• Hopelessness.

• Suicidal ideation or behavior.

• Anhedonia.

• Fatigue.

• Psychomotor retardation.

Interestingly, the proposed criteria do not include what the working group considered to be characteristics of both poles: irritability, indecisiveness, and psychomotor agitation (which is distinguished from goal-directed activity). In addition, the proposal does not include distractibility, "which I’ve come to believe is actually a feature of almost every patient anywhere on the bipolar spectrum," Dr. Frank said.

Insomnia or hypersomnia is another shared symptom not included in the specifier. Insomnia "is difficult to distinguish as a manic or depressive symptom," said Dr. Roy H. Perlis, director of the bipolar research program at Massachusetts General Hospital and instructor in psychiatry at Harvard Medical School, both in Boston.

Family aggregation, psychiatric history, concurrent psychiatric symptoms, and, particularly, treatment outcome were used as validators for the proposed specifier, Dr. Frank said. For example, in terms of treatment outcome, she added that a poor response to lithium and hypomanic symptoms during predominantly depressive states are associated with destabilization on antidepressants.

DSM-5 field trials are underway to assess the proposed criteria. The goal is to test the clinical acceptability and utility of the new constructs in both academic and practice settings. In addition, the reliability of diagnosis will be assessed in the academic component of the field trials. The clinics testing the mixed depression specifier include the Mayo Clinic, Rochester, Minn.; University of California,Los Angeles; the University of Texas Health Science Center at San Antonio; and the Veterans Affairs Medical Centers in Dallas and Houston.

Dr. Frank’s disclosures include Guilford Press and Servier International. Dr. Perlis’s disclosures include Concordant Rater Systems, Proteus Biomedical, and RIDVentures.

BOCA RATON, FLA.  – Proposed changes for the diagnosis of patients with mixed depressive episodes for the next edition of the Diagnostic and Statistical Manual of Mental Disorders will more closely reflect the patients psychiatrists see in their everyday practice, Ellen Frank, Ph.D., said.

The current DSM-IV-TR definition of a mixed episode requires that a patient meet full criteria for a manic episode and full criteria for a major depressive episode (except for duration) nearly every day for at least a 1-week period. "What did I think was wrong with this definition? As far as I’m concerned, these patients don’t exist," Dr. Frank said at the annual meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health.

I would argue that if you really carefully distinguish, for example, agitation from increased goal-directed activity, [and] if you really carefully distinguish the potential overlapping symptoms, these patients are about as rare as unicorns," Dr. Frank said.

"We thought the current criteria too restrictive, and they are rarely adhered to. When we say the patient is mixed, we rarely mean that the patient meets full criteria for both poles," said Dr. Frank, professor of psychiatry and psychology at the University of Pittsburgh. "This results in a lot of confusion, a lack of precision, and fails to identify [those] who are at risk of progression from unipolar to bipolar disorder."

Inappropriate treatment selection is another possibility with the DSM-IV-TR definition, said Dr. Frank, director of the Depression and Manic Depression Prevention Program at the Western Psychiatric Institute and Clinic in Pittsburgh, and a member of the DSM-5 Mood Disorders Work Group. In addition, "the consequence of the current definition in common use is that we underestimate suicide risk, because I do believe these patients are at excessive risk of suicide.

"This is a horrible state to be in, and we need to figure out how to do a better job of treating it."

What Dr. Frank and her collaborators on the working group propose for the DSM-5 is a mixed specifier that indicates the presence of symptoms – not the syndrome – of the opposite pole. The specifier would be applied to both episodes of mania and depression, and would be applicable in the context of both unipolar and bipolar lifetime diagnoses.

The psychiatric history of those who experience mixed states tend to include early onset of illness, multiple previous episodes, suicidal behavior, substance abuse, and other comorbid diagnoses that tend to be associated with bipolar disorder (such as panic).

Under the proposed construct, if a "mixed" patient is predominantly depressed, they meet full criteria for a major depressive episode and have at least three of the following nearly every day during the episode:

• Elevated mood.

• Decreased need for sleep (not insomnia).

• Goal-directed activity.

• Increased energy or visible hyperactivity (again, goal directed).

• Grandiosity.

• Accelerated speech.

• Racing thoughts.

If the patient is predominantly manic or hypomanic, they meet full criteria for the manic or hypomanic episode and feature at least three of the following:

• Subjective depression.

• Worry.

• Self-reproach or guilt.

• Negative evaluation of self.

• Hopelessness.

• Suicidal ideation or behavior.

• Anhedonia.

• Fatigue.

• Psychomotor retardation.

Interestingly, the proposed criteria do not include what the working group considered to be characteristics of both poles: irritability, indecisiveness, and psychomotor agitation (which is distinguished from goal-directed activity). In addition, the proposal does not include distractibility, "which I’ve come to believe is actually a feature of almost every patient anywhere on the bipolar spectrum," Dr. Frank said.

Insomnia or hypersomnia is another shared symptom not included in the specifier. Insomnia "is difficult to distinguish as a manic or depressive symptom," said Dr. Roy H. Perlis, director of the bipolar research program at Massachusetts General Hospital and instructor in psychiatry at Harvard Medical School, both in Boston.

Family aggregation, psychiatric history, concurrent psychiatric symptoms, and, particularly, treatment outcome were used as validators for the proposed specifier, Dr. Frank said. For example, in terms of treatment outcome, she added that a poor response to lithium and hypomanic symptoms during predominantly depressive states are associated with destabilization on antidepressants.

DSM-5 field trials are underway to assess the proposed criteria. The goal is to test the clinical acceptability and utility of the new constructs in both academic and practice settings. In addition, the reliability of diagnosis will be assessed in the academic component of the field trials. The clinics testing the mixed depression specifier include the Mayo Clinic, Rochester, Minn.; University of California,Los Angeles; the University of Texas Health Science Center at San Antonio; and the Veterans Affairs Medical Centers in Dallas and Houston.

Dr. Frank’s disclosures include Guilford Press and Servier International. Dr. Perlis’s disclosures include Concordant Rater Systems, Proteus Biomedical, and RIDVentures.

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

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

Dr. Karen D. Wagner

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dr. Karen D. Wagner

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dr. Karen D. Wagner

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dr. Karen D. Wagner

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dr. Karen D. Wagner

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dr. Karen D. Wagner

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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