Bipolar Disorder

A new study has proposed a more nuanced approach for the diagnosis and treatment of mixed episodes in bipolar I patients.

The study, conducted by Dr. Isabella Pacchiarotti and her colleagues implemented a "factor structure" approach toward acute mood episodes, with the goal of deconstructing mixed episodes in particular.

Researchers studied 187 bipolar I patients hospitalized for an acute episode – manic, depressive, or mixed – and diagnosed using DSM-IV-TR criteria. Patients were evaluated for manic, mixed, and depressive symptoms using the Brief Psychiatric Rating Scale (BPRS 4.0), the Hamilton Depression Rating Scale (HDRS-21), and the Young Mania Rating Scale (YMRS). Patients also completed a self-reported temperament evaluation after discharge, reported Dr. Pacchiarotti of the Bipolar Disorders Program at the Institute of Clinical Neuroscience, University of Barcelona.

A principal component factor analysis performed on the BPRS found five clinically relevant factors: psychosis (factor 1), euphoric mania (factor 2), "mixity" (factor 3), dysphoria (factor 4), and inhibited depression (factor 5).

Psychosis was characterized by positive loading for bizarre behavior, unusual thought content, hallucinations, disorientation, conceptual disorganization, mannerisms and posturing, distractibility, and self-neglect. Euphoric mania was characterized by elevated mood and grandiosity, with negative loading for depression, guilt, suicidality, somatic concern, tension, and anxiety. "Mixity" was defined by suicidality, excitement, motor hyperactivity, tension, and anxiety, with negative loading for motor retardation. Dysphoria had positive loading for hostility, uncooperativeness, and suspiciousness. Lastly, inhibited depression was defined by depression, guilt, motor retardation, emotional withdrawal, and blunted affect.

The investigators also performed an analysis to determine which factors were associated with depressive, manic, and mixed mood. No association was found between depressive episodes and any of the five factors. However, manic episodes were a predictor of psychosis and euphoric mania (factors 1 and 2), and mixed episodes were associated with mixity (factor 3). None of the episode types were predictors of dysphoria or inhibited depression (factors 3 and 4).

An important result of this study is the discovery of the mixity factor, which provides a more comprehensive profile of mixed episodes than does the conventional combination of manic and depressive symptoms. "Most mixed state scholars feel DSM-IV criteria for mixed states to be too restrictive," the authors wrote in their report. This study endorses the existence of two subtypes of mixed episodes: one defined by factor 3 and characterized by an anxious-agitated dimension, and the other defined by factor 4, characterized by irritability and dysphoria.

In addition, the authors provided recommendations for diagnostic improvements based on the findings of this paper. First, the DSM-IV excludes anxiety and includes psychomotor retardation in the diagnosis of mixed states, though the current research has found at least one group of bipolar I patients who presented with anxiety and did not have psychomotor retardation. The researchers suggested expanding the current diagnostic criteria to include this subset of bipolar patients.

The authors listed a few limitations to this study. First, the sample size was rather small. Second, this study analyzed only bipolar I patients, and did not assess individuals who were bipolar hypomanic or depressed with subsyndromal symptoms of opposite polarity. Third, this study did not evaluate patients over all phases of illness, only when they were admitted to the hospital. Fourth, most patients in this study were on medication when they were hospitalized, which might have affected results, particularly in factor 3. Lastly, further research is needed to generate more psychometric measures of mixed states, as few are currently available.

The authors of this study expressed hope that these new insights into the factor structure of bipolar episodes will result in improved diagnostic and treatment options in the future.

The study was funded by the several entities, including the Spanish Ministry of Economy and Competitiveness, and the Instituto de Salud Carlos III, Madrid.

[email protected]

A new study has proposed a more nuanced approach for the diagnosis and treatment of mixed episodes in bipolar I patients.

The study, conducted by Dr. Isabella Pacchiarotti and her colleagues implemented a "factor structure" approach toward acute mood episodes, with the goal of deconstructing mixed episodes in particular.

Researchers studied 187 bipolar I patients hospitalized for an acute episode – manic, depressive, or mixed – and diagnosed using DSM-IV-TR criteria. Patients were evaluated for manic, mixed, and depressive symptoms using the Brief Psychiatric Rating Scale (BPRS 4.0), the Hamilton Depression Rating Scale (HDRS-21), and the Young Mania Rating Scale (YMRS). Patients also completed a self-reported temperament evaluation after discharge, reported Dr. Pacchiarotti of the Bipolar Disorders Program at the Institute of Clinical Neuroscience, University of Barcelona.

A principal component factor analysis performed on the BPRS found five clinically relevant factors: psychosis (factor 1), euphoric mania (factor 2), "mixity" (factor 3), dysphoria (factor 4), and inhibited depression (factor 5).

Psychosis was characterized by positive loading for bizarre behavior, unusual thought content, hallucinations, disorientation, conceptual disorganization, mannerisms and posturing, distractibility, and self-neglect. Euphoric mania was characterized by elevated mood and grandiosity, with negative loading for depression, guilt, suicidality, somatic concern, tension, and anxiety. "Mixity" was defined by suicidality, excitement, motor hyperactivity, tension, and anxiety, with negative loading for motor retardation. Dysphoria had positive loading for hostility, uncooperativeness, and suspiciousness. Lastly, inhibited depression was defined by depression, guilt, motor retardation, emotional withdrawal, and blunted affect.

The investigators also performed an analysis to determine which factors were associated with depressive, manic, and mixed mood. No association was found between depressive episodes and any of the five factors. However, manic episodes were a predictor of psychosis and euphoric mania (factors 1 and 2), and mixed episodes were associated with mixity (factor 3). None of the episode types were predictors of dysphoria or inhibited depression (factors 3 and 4).

An important result of this study is the discovery of the mixity factor, which provides a more comprehensive profile of mixed episodes than does the conventional combination of manic and depressive symptoms. "Most mixed state scholars feel DSM-IV criteria for mixed states to be too restrictive," the authors wrote in their report. This study endorses the existence of two subtypes of mixed episodes: one defined by factor 3 and characterized by an anxious-agitated dimension, and the other defined by factor 4, characterized by irritability and dysphoria.

In addition, the authors provided recommendations for diagnostic improvements based on the findings of this paper. First, the DSM-IV excludes anxiety and includes psychomotor retardation in the diagnosis of mixed states, though the current research has found at least one group of bipolar I patients who presented with anxiety and did not have psychomotor retardation. The researchers suggested expanding the current diagnostic criteria to include this subset of bipolar patients.

The authors listed a few limitations to this study. First, the sample size was rather small. Second, this study analyzed only bipolar I patients, and did not assess individuals who were bipolar hypomanic or depressed with subsyndromal symptoms of opposite polarity. Third, this study did not evaluate patients over all phases of illness, only when they were admitted to the hospital. Fourth, most patients in this study were on medication when they were hospitalized, which might have affected results, particularly in factor 3. Lastly, further research is needed to generate more psychometric measures of mixed states, as few are currently available.

The authors of this study expressed hope that these new insights into the factor structure of bipolar episodes will result in improved diagnostic and treatment options in the future.

The study was funded by the several entities, including the Spanish Ministry of Economy and Competitiveness, and the Instituto de Salud Carlos III, Madrid.

[email protected]

A new study has proposed a more nuanced approach for the diagnosis and treatment of mixed episodes in bipolar I patients.

The study, conducted by Dr. Isabella Pacchiarotti and her colleagues implemented a "factor structure" approach toward acute mood episodes, with the goal of deconstructing mixed episodes in particular.

Researchers studied 187 bipolar I patients hospitalized for an acute episode – manic, depressive, or mixed – and diagnosed using DSM-IV-TR criteria. Patients were evaluated for manic, mixed, and depressive symptoms using the Brief Psychiatric Rating Scale (BPRS 4.0), the Hamilton Depression Rating Scale (HDRS-21), and the Young Mania Rating Scale (YMRS). Patients also completed a self-reported temperament evaluation after discharge, reported Dr. Pacchiarotti of the Bipolar Disorders Program at the Institute of Clinical Neuroscience, University of Barcelona.

A principal component factor analysis performed on the BPRS found five clinically relevant factors: psychosis (factor 1), euphoric mania (factor 2), "mixity" (factor 3), dysphoria (factor 4), and inhibited depression (factor 5).

Psychosis was characterized by positive loading for bizarre behavior, unusual thought content, hallucinations, disorientation, conceptual disorganization, mannerisms and posturing, distractibility, and self-neglect. Euphoric mania was characterized by elevated mood and grandiosity, with negative loading for depression, guilt, suicidality, somatic concern, tension, and anxiety. "Mixity" was defined by suicidality, excitement, motor hyperactivity, tension, and anxiety, with negative loading for motor retardation. Dysphoria had positive loading for hostility, uncooperativeness, and suspiciousness. Lastly, inhibited depression was defined by depression, guilt, motor retardation, emotional withdrawal, and blunted affect.

The investigators also performed an analysis to determine which factors were associated with depressive, manic, and mixed mood. No association was found between depressive episodes and any of the five factors. However, manic episodes were a predictor of psychosis and euphoric mania (factors 1 and 2), and mixed episodes were associated with mixity (factor 3). None of the episode types were predictors of dysphoria or inhibited depression (factors 3 and 4).

An important result of this study is the discovery of the mixity factor, which provides a more comprehensive profile of mixed episodes than does the conventional combination of manic and depressive symptoms. "Most mixed state scholars feel DSM-IV criteria for mixed states to be too restrictive," the authors wrote in their report. This study endorses the existence of two subtypes of mixed episodes: one defined by factor 3 and characterized by an anxious-agitated dimension, and the other defined by factor 4, characterized by irritability and dysphoria.

In addition, the authors provided recommendations for diagnostic improvements based on the findings of this paper. First, the DSM-IV excludes anxiety and includes psychomotor retardation in the diagnosis of mixed states, though the current research has found at least one group of bipolar I patients who presented with anxiety and did not have psychomotor retardation. The researchers suggested expanding the current diagnostic criteria to include this subset of bipolar patients.

The authors listed a few limitations to this study. First, the sample size was rather small. Second, this study analyzed only bipolar I patients, and did not assess individuals who were bipolar hypomanic or depressed with subsyndromal symptoms of opposite polarity. Third, this study did not evaluate patients over all phases of illness, only when they were admitted to the hospital. Fourth, most patients in this study were on medication when they were hospitalized, which might have affected results, particularly in factor 3. Lastly, further research is needed to generate more psychometric measures of mixed states, as few are currently available.

The authors of this study expressed hope that these new insights into the factor structure of bipolar episodes will result in improved diagnostic and treatment options in the future.

The study was funded by the several entities, including the Spanish Ministry of Economy and Competitiveness, and the Instituto de Salud Carlos III, Madrid.

[email protected]

Among youths with bipolar spectrum disorder, depressive symptoms more adversely affected their psychological functioning and quality of life than did manic symptoms, results from a small study showed.

"We hypothesized that the impact of bipolar depression in youth would be significant, but the lopsided nature of the results was more striking than expected," researchers led by Anna R. Van Meter reported online in the Journal of Affective Disorders. "Across numerous measures, depression was a significant predictor of negative outcomes, mania was not.

"This is not to say that mania is not impairing, our sample included only youth with bipolar disorder, so we cannot comment on the degree to which mania and/or depression caused problems for youth with bipolar disorder, relative to youth without mood disturbance. Still, at the very least, these findings suggest that the collective focus on mania, often it seems at the exclusion of depression, may be misguided."

For the study, Ms. Van Meter and her associates recruited 54 youths aged 7-13 years old who met DSM-IV-TR criteria for bipolar spectrum disorders from a clinic in a large Midwestern city (J. Affect. Dis. 2013 June 12 [doi:10.1016/j.jad.2013.05.039]).

They used regression analyses to evaluate clinician and parent reports of manic and depressive symptoms from numerous survey instruments in an effort to determine how each set of symptoms affected child functioning. Measures included the Washington University Schedule for Affective Disorders, the Children’s Global Assessment Scale, the Young Mania Rating Scale, and the Child Bipolar Depression Rating Scale.

The mean age of the 54 study participants was 9 years, 42% were female, and more than half (60%) were of white European descent. Diagnoses included bipolar disorder not otherwise specified (57%), bipolar I disorder (41%), and bipolar II disorder (2%).

Parent-rated child depression symptoms were associated with problem behaviors (P less than .05) and lower quality of life (P less than .001), while clinician-rated child depression was associated with greater psychiatric illness (P less than .05), lower child self-concept (P less than .001), lower quality of life (P less than .05), hopelessness (P less than .05), and suicidal ideation (P less than .05), reported Ms. Van Meter of the department of psychology at the University of North Carolina, Chapel Hill, and her associates.

At the same time, parent-rated mania was associated with better self-esteem (P less than 0.05) and physical well-being (P less than .05), while clinician-rated mania was associated with greater psychiatric illness (P less than .05) and physical well-being (P less than .05).

"Which specific aspects of bipolar depression cause decreased quality of life and through what mechanisms mania provides protection against functional impairment remain important areas for study," the researchers concluded. "In general, the identification of how different symptom constellations in pediatric bipolar disorder relate to functional impairment should be an important mission for our research agenda. Thus, this study introduces new questions to guide researchers in developing a more in-depth understanding of this complex disorder and raises awareness of the debilitating effects of bipolar depression in youth."

They acknowledged certain limitations of the study. One is that specific outcomes predicted by parent- and clinician-rated symptoms vary.

The study was supported by the National Institute of Mental Health. The researchers stated that they had no relevant financial conflicts to disclose.

[email protected]

Among youths with bipolar spectrum disorder, depressive symptoms more adversely affected their psychological functioning and quality of life than did manic symptoms, results from a small study showed.

"We hypothesized that the impact of bipolar depression in youth would be significant, but the lopsided nature of the results was more striking than expected," researchers led by Anna R. Van Meter reported online in the Journal of Affective Disorders. "Across numerous measures, depression was a significant predictor of negative outcomes, mania was not.

"This is not to say that mania is not impairing, our sample included only youth with bipolar disorder, so we cannot comment on the degree to which mania and/or depression caused problems for youth with bipolar disorder, relative to youth without mood disturbance. Still, at the very least, these findings suggest that the collective focus on mania, often it seems at the exclusion of depression, may be misguided."

For the study, Ms. Van Meter and her associates recruited 54 youths aged 7-13 years old who met DSM-IV-TR criteria for bipolar spectrum disorders from a clinic in a large Midwestern city (J. Affect. Dis. 2013 June 12 [doi:10.1016/j.jad.2013.05.039]).

They used regression analyses to evaluate clinician and parent reports of manic and depressive symptoms from numerous survey instruments in an effort to determine how each set of symptoms affected child functioning. Measures included the Washington University Schedule for Affective Disorders, the Children’s Global Assessment Scale, the Young Mania Rating Scale, and the Child Bipolar Depression Rating Scale.

The mean age of the 54 study participants was 9 years, 42% were female, and more than half (60%) were of white European descent. Diagnoses included bipolar disorder not otherwise specified (57%), bipolar I disorder (41%), and bipolar II disorder (2%).

Parent-rated child depression symptoms were associated with problem behaviors (P less than .05) and lower quality of life (P less than .001), while clinician-rated child depression was associated with greater psychiatric illness (P less than .05), lower child self-concept (P less than .001), lower quality of life (P less than .05), hopelessness (P less than .05), and suicidal ideation (P less than .05), reported Ms. Van Meter of the department of psychology at the University of North Carolina, Chapel Hill, and her associates.

At the same time, parent-rated mania was associated with better self-esteem (P less than 0.05) and physical well-being (P less than .05), while clinician-rated mania was associated with greater psychiatric illness (P less than .05) and physical well-being (P less than .05).

"Which specific aspects of bipolar depression cause decreased quality of life and through what mechanisms mania provides protection against functional impairment remain important areas for study," the researchers concluded. "In general, the identification of how different symptom constellations in pediatric bipolar disorder relate to functional impairment should be an important mission for our research agenda. Thus, this study introduces new questions to guide researchers in developing a more in-depth understanding of this complex disorder and raises awareness of the debilitating effects of bipolar depression in youth."

They acknowledged certain limitations of the study. One is that specific outcomes predicted by parent- and clinician-rated symptoms vary.

The study was supported by the National Institute of Mental Health. The researchers stated that they had no relevant financial conflicts to disclose.

[email protected]

Among youths with bipolar spectrum disorder, depressive symptoms more adversely affected their psychological functioning and quality of life than did manic symptoms, results from a small study showed.

"We hypothesized that the impact of bipolar depression in youth would be significant, but the lopsided nature of the results was more striking than expected," researchers led by Anna R. Van Meter reported online in the Journal of Affective Disorders. "Across numerous measures, depression was a significant predictor of negative outcomes, mania was not.

"This is not to say that mania is not impairing, our sample included only youth with bipolar disorder, so we cannot comment on the degree to which mania and/or depression caused problems for youth with bipolar disorder, relative to youth without mood disturbance. Still, at the very least, these findings suggest that the collective focus on mania, often it seems at the exclusion of depression, may be misguided."

For the study, Ms. Van Meter and her associates recruited 54 youths aged 7-13 years old who met DSM-IV-TR criteria for bipolar spectrum disorders from a clinic in a large Midwestern city (J. Affect. Dis. 2013 June 12 [doi:10.1016/j.jad.2013.05.039]).

They used regression analyses to evaluate clinician and parent reports of manic and depressive symptoms from numerous survey instruments in an effort to determine how each set of symptoms affected child functioning. Measures included the Washington University Schedule for Affective Disorders, the Children’s Global Assessment Scale, the Young Mania Rating Scale, and the Child Bipolar Depression Rating Scale.

The mean age of the 54 study participants was 9 years, 42% were female, and more than half (60%) were of white European descent. Diagnoses included bipolar disorder not otherwise specified (57%), bipolar I disorder (41%), and bipolar II disorder (2%).

Parent-rated child depression symptoms were associated with problem behaviors (P less than .05) and lower quality of life (P less than .001), while clinician-rated child depression was associated with greater psychiatric illness (P less than .05), lower child self-concept (P less than .001), lower quality of life (P less than .05), hopelessness (P less than .05), and suicidal ideation (P less than .05), reported Ms. Van Meter of the department of psychology at the University of North Carolina, Chapel Hill, and her associates.

At the same time, parent-rated mania was associated with better self-esteem (P less than 0.05) and physical well-being (P less than .05), while clinician-rated mania was associated with greater psychiatric illness (P less than .05) and physical well-being (P less than .05).

"Which specific aspects of bipolar depression cause decreased quality of life and through what mechanisms mania provides protection against functional impairment remain important areas for study," the researchers concluded. "In general, the identification of how different symptom constellations in pediatric bipolar disorder relate to functional impairment should be an important mission for our research agenda. Thus, this study introduces new questions to guide researchers in developing a more in-depth understanding of this complex disorder and raises awareness of the debilitating effects of bipolar depression in youth."

They acknowledged certain limitations of the study. One is that specific outcomes predicted by parent- and clinician-rated symptoms vary.

The study was supported by the National Institute of Mental Health. The researchers stated that they had no relevant financial conflicts to disclose.

[email protected]

Women and men with bipolar disorder were more likely to die prematurely than were those without bipolar disorder, according to results from a Swedish national cohort study involving nearly 6.6 million adults.

After adjustment for age, marital status, educational level, employment status, and income, all-cause mortality among the 6,618 adults with bipolar disorder in the cohort was increased twofold for both women (adjusted hazard ratio, 2.34) and men (AHR, 2.03), who died an average of 9.0 and 8.5 years earlier, respectively, did than those without bipolar disorder, according to Dr. Casey Crump of Stanford (Calif.) University, and his colleagues.

Those with bipolar disorder died prematurely from various causes, including cardiovascular disease, diabetes, chronic obstructive pulmonary disease (COPD), influenza or pneumonia, unintentional injuries, and suicide. Among women, stroke and cancer (particularly colon cancer) were also among the causes of premature death. Suicide was a particular risk for both women and men, who had 10-fold and 8-fold increases in risk, respectively (AHRs, 10.37 and 8.09), but the life expectancy differences were not fully explained by unnatural deaths, the investigators reported July 17 online in JAMA Psychiatry.

The most significant causes of death were influenza or pneumonia (3.7- and 4.4-fold increased risk for women and men, respectively), diabetes (3.6- and 2.6-fold increased risk, respectively), and COPD (2.9- and 2.6-fold increased risk).

In a separate model, the potential mediating effect of substance use disorders also was evaluated, and the effect was found to be modest, the investigators noted.

The associations between the various conditions and premature death were weakest for chronic diseases in those with a prior diagnosis, compared with those without a prior diagnosis (AHRs, 1.40 vs. 2.38), suggesting that earlier medical diagnosis and treatment might attenuate the increased mortality risk among affected individuals, they said (JAMA Psychiatry 2013 July 17 [doi: 10.1001/jamapsychiatry.2013.1394]).

"More complete provision of primary, preventive medical care among bipolar disorder patients is needed to reduce early mortality in this vulnerable population," they said, noting that multiple underlying mechanisms, including lifestyle factors, pathophysiologic mechanisms, genetic factors, and certain treatments for bipolar disorder, contribute to the disparities.

"The current study found evidence of modestly increased mortality among bipolar disorder patients who used carbamazepine, risperidone, or valproic acid or who solely used olanzapine, whereas users of aripiprazole, quetiapine, or lamotrigine had modestly reduced mortality compared with those who solely used lithium," they said.

However, consistent with prior research, those who used none of these medications had even higher rates of all-cause mortality – and twice the suicide risk – of those who used medication.

Study participants were 3,918 women and 2,700 men aged 20 years or older who lived in Sweden for at least 2 years as of Jan. 1, 2003. They were followed up to assess for physical comorbidities and mortality for 7 years. Bipolar disorder in the cohort was identified by any diagnosis during the preceding 2 years, and by the use of specific medications commonly used for bipolar disorder maintenance treatment.

The findings of this study, which is among the first to examine the association between bipolar disorder and mortality using complete diagnoses for a national population, adds to the increasing knowledge about factors that contribute to premature mortality in patients with bipolar disorder, but it is unclear to what extent the findings can be generalized to other health care systems, the investigators said.

"The substantial health disparities we found between bipolar disorder patients and the rest of the Swedish population may be even larger in other countries without universal health care," they noted.

This study was supported by a grant from the National Institute on Drug Abuse and an Agreement on Medical Training and Research (Lund, Sweden) project grant. The authors reported having no disclosures.

Women and men with bipolar disorder were more likely to die prematurely than were those without bipolar disorder, according to results from a Swedish national cohort study involving nearly 6.6 million adults.

After adjustment for age, marital status, educational level, employment status, and income, all-cause mortality among the 6,618 adults with bipolar disorder in the cohort was increased twofold for both women (adjusted hazard ratio, 2.34) and men (AHR, 2.03), who died an average of 9.0 and 8.5 years earlier, respectively, did than those without bipolar disorder, according to Dr. Casey Crump of Stanford (Calif.) University, and his colleagues.

Those with bipolar disorder died prematurely from various causes, including cardiovascular disease, diabetes, chronic obstructive pulmonary disease (COPD), influenza or pneumonia, unintentional injuries, and suicide. Among women, stroke and cancer (particularly colon cancer) were also among the causes of premature death. Suicide was a particular risk for both women and men, who had 10-fold and 8-fold increases in risk, respectively (AHRs, 10.37 and 8.09), but the life expectancy differences were not fully explained by unnatural deaths, the investigators reported July 17 online in JAMA Psychiatry.

The most significant causes of death were influenza or pneumonia (3.7- and 4.4-fold increased risk for women and men, respectively), diabetes (3.6- and 2.6-fold increased risk, respectively), and COPD (2.9- and 2.6-fold increased risk).

In a separate model, the potential mediating effect of substance use disorders also was evaluated, and the effect was found to be modest, the investigators noted.

The associations between the various conditions and premature death were weakest for chronic diseases in those with a prior diagnosis, compared with those without a prior diagnosis (AHRs, 1.40 vs. 2.38), suggesting that earlier medical diagnosis and treatment might attenuate the increased mortality risk among affected individuals, they said (JAMA Psychiatry 2013 July 17 [doi: 10.1001/jamapsychiatry.2013.1394]).

"More complete provision of primary, preventive medical care among bipolar disorder patients is needed to reduce early mortality in this vulnerable population," they said, noting that multiple underlying mechanisms, including lifestyle factors, pathophysiologic mechanisms, genetic factors, and certain treatments for bipolar disorder, contribute to the disparities.

"The current study found evidence of modestly increased mortality among bipolar disorder patients who used carbamazepine, risperidone, or valproic acid or who solely used olanzapine, whereas users of aripiprazole, quetiapine, or lamotrigine had modestly reduced mortality compared with those who solely used lithium," they said.

However, consistent with prior research, those who used none of these medications had even higher rates of all-cause mortality – and twice the suicide risk – of those who used medication.

Study participants were 3,918 women and 2,700 men aged 20 years or older who lived in Sweden for at least 2 years as of Jan. 1, 2003. They were followed up to assess for physical comorbidities and mortality for 7 years. Bipolar disorder in the cohort was identified by any diagnosis during the preceding 2 years, and by the use of specific medications commonly used for bipolar disorder maintenance treatment.

The findings of this study, which is among the first to examine the association between bipolar disorder and mortality using complete diagnoses for a national population, adds to the increasing knowledge about factors that contribute to premature mortality in patients with bipolar disorder, but it is unclear to what extent the findings can be generalized to other health care systems, the investigators said.

"The substantial health disparities we found between bipolar disorder patients and the rest of the Swedish population may be even larger in other countries without universal health care," they noted.

This study was supported by a grant from the National Institute on Drug Abuse and an Agreement on Medical Training and Research (Lund, Sweden) project grant. The authors reported having no disclosures.

Women and men with bipolar disorder were more likely to die prematurely than were those without bipolar disorder, according to results from a Swedish national cohort study involving nearly 6.6 million adults.

After adjustment for age, marital status, educational level, employment status, and income, all-cause mortality among the 6,618 adults with bipolar disorder in the cohort was increased twofold for both women (adjusted hazard ratio, 2.34) and men (AHR, 2.03), who died an average of 9.0 and 8.5 years earlier, respectively, did than those without bipolar disorder, according to Dr. Casey Crump of Stanford (Calif.) University, and his colleagues.

Those with bipolar disorder died prematurely from various causes, including cardiovascular disease, diabetes, chronic obstructive pulmonary disease (COPD), influenza or pneumonia, unintentional injuries, and suicide. Among women, stroke and cancer (particularly colon cancer) were also among the causes of premature death. Suicide was a particular risk for both women and men, who had 10-fold and 8-fold increases in risk, respectively (AHRs, 10.37 and 8.09), but the life expectancy differences were not fully explained by unnatural deaths, the investigators reported July 17 online in JAMA Psychiatry.

The most significant causes of death were influenza or pneumonia (3.7- and 4.4-fold increased risk for women and men, respectively), diabetes (3.6- and 2.6-fold increased risk, respectively), and COPD (2.9- and 2.6-fold increased risk).

In a separate model, the potential mediating effect of substance use disorders also was evaluated, and the effect was found to be modest, the investigators noted.

The associations between the various conditions and premature death were weakest for chronic diseases in those with a prior diagnosis, compared with those without a prior diagnosis (AHRs, 1.40 vs. 2.38), suggesting that earlier medical diagnosis and treatment might attenuate the increased mortality risk among affected individuals, they said (JAMA Psychiatry 2013 July 17 [doi: 10.1001/jamapsychiatry.2013.1394]).

"More complete provision of primary, preventive medical care among bipolar disorder patients is needed to reduce early mortality in this vulnerable population," they said, noting that multiple underlying mechanisms, including lifestyle factors, pathophysiologic mechanisms, genetic factors, and certain treatments for bipolar disorder, contribute to the disparities.

"The current study found evidence of modestly increased mortality among bipolar disorder patients who used carbamazepine, risperidone, or valproic acid or who solely used olanzapine, whereas users of aripiprazole, quetiapine, or lamotrigine had modestly reduced mortality compared with those who solely used lithium," they said.

However, consistent with prior research, those who used none of these medications had even higher rates of all-cause mortality – and twice the suicide risk – of those who used medication.

Study participants were 3,918 women and 2,700 men aged 20 years or older who lived in Sweden for at least 2 years as of Jan. 1, 2003. They were followed up to assess for physical comorbidities and mortality for 7 years. Bipolar disorder in the cohort was identified by any diagnosis during the preceding 2 years, and by the use of specific medications commonly used for bipolar disorder maintenance treatment.

The findings of this study, which is among the first to examine the association between bipolar disorder and mortality using complete diagnoses for a national population, adds to the increasing knowledge about factors that contribute to premature mortality in patients with bipolar disorder, but it is unclear to what extent the findings can be generalized to other health care systems, the investigators said.

"The substantial health disparities we found between bipolar disorder patients and the rest of the Swedish population may be even larger in other countries without universal health care," they noted.

This study was supported by a grant from the National Institute on Drug Abuse and an Agreement on Medical Training and Research (Lund, Sweden) project grant. The authors reported having no disclosures.

The underlying neural mechanisms for processing affective stimuli appear to differ in patients with bipolar disorder II, compared with those of healthy controls, a study has shown.

Both functional MRI scans during patients’ exposure to facial expressions and an overt task of identifying fearful or happy faces revealed differences in bipolar patients’ processing of emotional information relative to healthy controls, reported Kelly A. Sagar and her associates at McLean Hospital, Belmont, Mass., in the Journal of Affective Disorders (2013 May 30 [doi:10.1016/j.jad.2013.05.019]).

Ms. Sagar’s team wrote that their findings suggest that bipolar I patients "have difficulties with the identification of certain emotional expressions," potentially resulting "in an inability to appropriately read social cues, which often leads to miscommunication, misinterpretation, and compromised interpersonal relationships."

The researchers assessed the affective processing of 23 bipolar I patients and 18 healthy controls in two separate tasks. The bipolar I patients, with a mean age of 26.65 (plus or minus 6.65) and a mean bipolar disorder onset age of 16.5 (plus or minus 3.65) were primarily euthymic at the time of the study, and their pharmacotherapeutic regimens had been stable for at least 12 weeks before the study began.

Four bipolar patients were unmedicated at the time of the study, four were taking antidepressants, four were taking benzodiazepines, 11 were taking antipsychotics, and 17 were taking mood stabilizers. The healthy controls tended to be younger, with a mean age of 23.11 (plus or minus 3.15), but the controls’ years of education (15.53 plus or minus 21.22 ) were similar to those of the bipolar participants (14.57 plus or minus 1.68).

During the functional MRI task, the participants completed a backward-masked affect paradigm in which they viewed black and white photographs of male and female faces with different expressions, shown for 30 milliseconds each. The two affective conditions were fearful and happy, alternated with neutral faces and with neutral masks shown between each face for 170 milliseconds.

Ms. Sagar’s team reported results for both single sample analyses and contrast analyses (subtracting one group map from the other for each face condition).

In the single sample analyses, the patients with bipolar disorder showed altered activation in the amygdala and increased activation in the anterior cingulate and dorsolateral prefrontal cortex during the fear condition, compared with the controls. The bipolar patients’ activation patterns in these three regions were more diffuse during the happy condition than in the controls.

In the contrast analyses, relative to controls, bipolar patients showed increased activation in the anterior cingulate cortex, bilateral amygdala, and dorsolateral prefrontal cortex during the fear condition and higher activation in the subgenual anterior cingulate, right dorsolateral prefrontal cortex, and left amygdala during the happy condition. The controls showed higher activation in the midcingulate and left dorsolateral prefrontal cortex during the happy condition, compared with the participants with bipolar disorder.

After the functional MRI scan, participants completed the computerized Facial Expression of Emotion Stimuli and Test, in which they had to identify the most closely represented emotion (anger, disgust, fear, happiness, sadness, or surprise) for 60 faces shown for 5 seconds each.

The bipolar participants identified fewer of the fearful faces, with an average 68.91% accuracy (standard deviation = 21.74), compared with 80% accuracy (SD = 14.14) among the controls. Identification of the happy faces, however, was comparable between the groups, with 97.39% accuracy (SD = 7.51) among the bipolar participants and 98.89% accuracy (SD = 3.23) among the controls.

The researchers noted that the functional MRI scan results revealed that the differences in emotional processing between bipolar patients and healthy controls occurred when the stimuli were shown "below the level of conscious awareness, suggesting a disruption early in the neural circuit responsible for affective processing." These findings, along with the greater difficulty bipolar patients had in identifying fearful faces during the overt task, corroborate similar findings in other studies, including a meta-analysis finding impairments among bipolar patients in recognizing facial emotions.

"Given the behavioral alterations and difficulty in inhibiting inappropriate responses often seen in patients with [bipolar disorder], these findings may have implications for reading cues in social situations, which may result in negative consequences," the authors wrote.

The study was limited by the moderate number of participants, the statistically significant but likely not biologically significant, age differences between the two groups, and the inability to be certain whether medication status could have affected the results.

The study was funded by the Jim and Pat Poitras Foundation and by a National Institute on Drug Abuse grant. The authors reported that they had no relevant financial disclosures.

The underlying neural mechanisms for processing affective stimuli appear to differ in patients with bipolar disorder II, compared with those of healthy controls, a study has shown.

Both functional MRI scans during patients’ exposure to facial expressions and an overt task of identifying fearful or happy faces revealed differences in bipolar patients’ processing of emotional information relative to healthy controls, reported Kelly A. Sagar and her associates at McLean Hospital, Belmont, Mass., in the Journal of Affective Disorders (2013 May 30 [doi:10.1016/j.jad.2013.05.019]).

Ms. Sagar’s team wrote that their findings suggest that bipolar I patients "have difficulties with the identification of certain emotional expressions," potentially resulting "in an inability to appropriately read social cues, which often leads to miscommunication, misinterpretation, and compromised interpersonal relationships."

The researchers assessed the affective processing of 23 bipolar I patients and 18 healthy controls in two separate tasks. The bipolar I patients, with a mean age of 26.65 (plus or minus 6.65) and a mean bipolar disorder onset age of 16.5 (plus or minus 3.65) were primarily euthymic at the time of the study, and their pharmacotherapeutic regimens had been stable for at least 12 weeks before the study began.

Four bipolar patients were unmedicated at the time of the study, four were taking antidepressants, four were taking benzodiazepines, 11 were taking antipsychotics, and 17 were taking mood stabilizers. The healthy controls tended to be younger, with a mean age of 23.11 (plus or minus 3.15), but the controls’ years of education (15.53 plus or minus 21.22 ) were similar to those of the bipolar participants (14.57 plus or minus 1.68).

During the functional MRI task, the participants completed a backward-masked affect paradigm in which they viewed black and white photographs of male and female faces with different expressions, shown for 30 milliseconds each. The two affective conditions were fearful and happy, alternated with neutral faces and with neutral masks shown between each face for 170 milliseconds.

Ms. Sagar’s team reported results for both single sample analyses and contrast analyses (subtracting one group map from the other for each face condition).

In the single sample analyses, the patients with bipolar disorder showed altered activation in the amygdala and increased activation in the anterior cingulate and dorsolateral prefrontal cortex during the fear condition, compared with the controls. The bipolar patients’ activation patterns in these three regions were more diffuse during the happy condition than in the controls.

In the contrast analyses, relative to controls, bipolar patients showed increased activation in the anterior cingulate cortex, bilateral amygdala, and dorsolateral prefrontal cortex during the fear condition and higher activation in the subgenual anterior cingulate, right dorsolateral prefrontal cortex, and left amygdala during the happy condition. The controls showed higher activation in the midcingulate and left dorsolateral prefrontal cortex during the happy condition, compared with the participants with bipolar disorder.

After the functional MRI scan, participants completed the computerized Facial Expression of Emotion Stimuli and Test, in which they had to identify the most closely represented emotion (anger, disgust, fear, happiness, sadness, or surprise) for 60 faces shown for 5 seconds each.

The bipolar participants identified fewer of the fearful faces, with an average 68.91% accuracy (standard deviation = 21.74), compared with 80% accuracy (SD = 14.14) among the controls. Identification of the happy faces, however, was comparable between the groups, with 97.39% accuracy (SD = 7.51) among the bipolar participants and 98.89% accuracy (SD = 3.23) among the controls.

The researchers noted that the functional MRI scan results revealed that the differences in emotional processing between bipolar patients and healthy controls occurred when the stimuli were shown "below the level of conscious awareness, suggesting a disruption early in the neural circuit responsible for affective processing." These findings, along with the greater difficulty bipolar patients had in identifying fearful faces during the overt task, corroborate similar findings in other studies, including a meta-analysis finding impairments among bipolar patients in recognizing facial emotions.

"Given the behavioral alterations and difficulty in inhibiting inappropriate responses often seen in patients with [bipolar disorder], these findings may have implications for reading cues in social situations, which may result in negative consequences," the authors wrote.

The study was limited by the moderate number of participants, the statistically significant but likely not biologically significant, age differences between the two groups, and the inability to be certain whether medication status could have affected the results.

The study was funded by the Jim and Pat Poitras Foundation and by a National Institute on Drug Abuse grant. The authors reported that they had no relevant financial disclosures.

The underlying neural mechanisms for processing affective stimuli appear to differ in patients with bipolar disorder II, compared with those of healthy controls, a study has shown.

Both functional MRI scans during patients’ exposure to facial expressions and an overt task of identifying fearful or happy faces revealed differences in bipolar patients’ processing of emotional information relative to healthy controls, reported Kelly A. Sagar and her associates at McLean Hospital, Belmont, Mass., in the Journal of Affective Disorders (2013 May 30 [doi:10.1016/j.jad.2013.05.019]).

Ms. Sagar’s team wrote that their findings suggest that bipolar I patients "have difficulties with the identification of certain emotional expressions," potentially resulting "in an inability to appropriately read social cues, which often leads to miscommunication, misinterpretation, and compromised interpersonal relationships."

The researchers assessed the affective processing of 23 bipolar I patients and 18 healthy controls in two separate tasks. The bipolar I patients, with a mean age of 26.65 (plus or minus 6.65) and a mean bipolar disorder onset age of 16.5 (plus or minus 3.65) were primarily euthymic at the time of the study, and their pharmacotherapeutic regimens had been stable for at least 12 weeks before the study began.

Four bipolar patients were unmedicated at the time of the study, four were taking antidepressants, four were taking benzodiazepines, 11 were taking antipsychotics, and 17 were taking mood stabilizers. The healthy controls tended to be younger, with a mean age of 23.11 (plus or minus 3.15), but the controls’ years of education (15.53 plus or minus 21.22 ) were similar to those of the bipolar participants (14.57 plus or minus 1.68).

During the functional MRI task, the participants completed a backward-masked affect paradigm in which they viewed black and white photographs of male and female faces with different expressions, shown for 30 milliseconds each. The two affective conditions were fearful and happy, alternated with neutral faces and with neutral masks shown between each face for 170 milliseconds.

Ms. Sagar’s team reported results for both single sample analyses and contrast analyses (subtracting one group map from the other for each face condition).

In the single sample analyses, the patients with bipolar disorder showed altered activation in the amygdala and increased activation in the anterior cingulate and dorsolateral prefrontal cortex during the fear condition, compared with the controls. The bipolar patients’ activation patterns in these three regions were more diffuse during the happy condition than in the controls.

In the contrast analyses, relative to controls, bipolar patients showed increased activation in the anterior cingulate cortex, bilateral amygdala, and dorsolateral prefrontal cortex during the fear condition and higher activation in the subgenual anterior cingulate, right dorsolateral prefrontal cortex, and left amygdala during the happy condition. The controls showed higher activation in the midcingulate and left dorsolateral prefrontal cortex during the happy condition, compared with the participants with bipolar disorder.

After the functional MRI scan, participants completed the computerized Facial Expression of Emotion Stimuli and Test, in which they had to identify the most closely represented emotion (anger, disgust, fear, happiness, sadness, or surprise) for 60 faces shown for 5 seconds each.

The bipolar participants identified fewer of the fearful faces, with an average 68.91% accuracy (standard deviation = 21.74), compared with 80% accuracy (SD = 14.14) among the controls. Identification of the happy faces, however, was comparable between the groups, with 97.39% accuracy (SD = 7.51) among the bipolar participants and 98.89% accuracy (SD = 3.23) among the controls.

The researchers noted that the functional MRI scan results revealed that the differences in emotional processing between bipolar patients and healthy controls occurred when the stimuli were shown "below the level of conscious awareness, suggesting a disruption early in the neural circuit responsible for affective processing." These findings, along with the greater difficulty bipolar patients had in identifying fearful faces during the overt task, corroborate similar findings in other studies, including a meta-analysis finding impairments among bipolar patients in recognizing facial emotions.

"Given the behavioral alterations and difficulty in inhibiting inappropriate responses often seen in patients with [bipolar disorder], these findings may have implications for reading cues in social situations, which may result in negative consequences," the authors wrote.

The study was limited by the moderate number of participants, the statistically significant but likely not biologically significant, age differences between the two groups, and the inability to be certain whether medication status could have affected the results.

The study was funded by the Jim and Pat Poitras Foundation and by a National Institute on Drug Abuse grant. The authors reported that they had no relevant financial disclosures.

CHICAGO – Treatment with antipsychotic agents in acute psychiatric inpatient units is not associated with increased blood glucose levels, according to a multicenter study.

"This finding is contrary to what many of us may have previously considered," Dr. Dawn D. Smiley observed in presenting the study findings at the annual scientific sessions of the American Diabetes Association.

A well-recognized association exists between the use of antipsychotic agents and an increased prevalence of diabetes and hyperglycemia, although it remains unclear whether the relationship is causal. The association is especially strong for the atypical or second-generation antipsychotics, which account for more than 90% of all antipsychotic use and are among the top-selling prescription drugs in the United States. Indeed, the Food and Drug Administration has for a decade required the product labeling for all atypical antipsychotics to include a warning about the risks of hyperglycemia and diabetes.

But most data on antipsychotic-associated diabetes come from long-term studies, which show that diabetes, when it occurs, most often does so within the first 6 months on the medication. Little is known about the acute impact of antipsychotic agents on blood glucose levels and clinical outcomes in patients admitted to acute psychiatric units for stays averaging a few weeks. This information gap provided the rationale for Dr. Smiley’s study.

She presented a chart review of 1,212 patients admitted to three acute inpatient psychiatric units in inner-city Atlanta during 2008. The mean age of the patients was 57 years, they had a mean body mass index of 27 kg/m², and the mean daily blood glucose concentration was 122 mg/dL during their stay. Twenty-one percent of the patients had a history of diabetes, and 6% had new hyperglycemia at admission. The most common primary diagnoses on admission were suicidal ideation in 28% of patients, a primary psychotic disorder in 27%, and depression in 16%.

Thirty-seven percent of patients had no prior experience with antipsychotic agents but were newly started on an antipsychotic during their acute inpatient stay. An additional 38% had been on antipsychotic therapy prior to admission and continued on it while hospitalized. Twenty-five percent of patients had never been treated with antipsychotic agents and were not during their hospitalization. Fifty-two percent of patients were treated with atypical antipsychotic agents during their inpatient stay, 17% received both atypical and typical antipsychotics, and 6% got typical antipsychotics only, explained Dr. Smiley, an endocrinologist at Emory University, Atlanta.

She sought answers to three research questions:

• Does prior exposure to antipsychotic therapy affect inpatient blood glucose levels or clinical outcome measures? Mean psychiatric inpatient length of stay was significantly shorter for patients never exposed to antipsychotics, at 9.5 days, compared with 14.2 days in patients who continued on their previous antipsychotic regimen and 13.7 days in antipsychotic-naive patients started on an antipsychotic for the first time. The most likely explanation for the longer stays in patients on antipsychotic therapy was the need to monitor them for side effects, according to Dr. Smiley.

Importantly, mean daily blood glucose concentrations during psychiatric hospitalization did not differ between patients never exposed to antipsychotic agents, those started on an antipsychotic for the first time during their hospitalization, and patients continued on their previous antipsychotics.

• Does the type of antipsychotic agent used during the acute inpatient admission affect blood glucose levels or clinical outcomes?

Mean daily blood glucose levels were similar regardless of whether patients were on atypical antipsychotics, typical antipsychotics, or both. The mean hemoglobin A_1c level was 7.3% in all three groups of antipsychotic-treated patients. However, the rate of medical complications during psychiatric hospitalization was significantly higher among patients on atypical agents, at 23%, compared with 17% in patients on typical antipsychotics and 13% in those on both.

Three percent of patients on atypical antipsychotics-only required transfer to a medical unit for treatment of a complication that arose during psychiatric hospitalization. That was also true for 3% of patients on combined atypical/typical antipsychotic therapy. In contrast, none of the relatively few patients on typical antipsychotics-only required transfer to a medical unit. It’s worth noting that all atypical antipsychotics are not alike in terms of the strength of their association with diabetes. Most antipsychotic-treated patients in this study got olanzapine (Zyprexa) or clozapine (Clozaril). Newer, less diabetogenic atypical agents were less frequently used in this largely indigent population.

• Does a history of diabetes or new hyperglycemia at admission affect outcome measures? Not unexpectedly, patients with a history of diabetes prior to admission had a significantly higher rate of medical complications during their psychiatric inpatient stay: a 28% rate, compared with 22% in patients with no history of diabetes but with hyperglycemia at admission and 20% in patients with neither metabolic abnormality. The most common complication in patients with a history of diabetes was urinary tract infection.

Again unsurprisingly, patients with a history of diabetes had a significantly higher rate of transfer to a medical unit because of medical complications: 5%, compared with no transfers in patients with new hyperglycemia at admission and a 1% transfer rate in patients with neither metabolic abnormality.

Dr. Smiley reported that her research funding came from the National Institutes of Health, Sanofi-Aventis, and Merck.

[email protected]

CHICAGO – Treatment with antipsychotic agents in acute psychiatric inpatient units is not associated with increased blood glucose levels, according to a multicenter study.

"This finding is contrary to what many of us may have previously considered," Dr. Dawn D. Smiley observed in presenting the study findings at the annual scientific sessions of the American Diabetes Association.

A well-recognized association exists between the use of antipsychotic agents and an increased prevalence of diabetes and hyperglycemia, although it remains unclear whether the relationship is causal. The association is especially strong for the atypical or second-generation antipsychotics, which account for more than 90% of all antipsychotic use and are among the top-selling prescription drugs in the United States. Indeed, the Food and Drug Administration has for a decade required the product labeling for all atypical antipsychotics to include a warning about the risks of hyperglycemia and diabetes.

But most data on antipsychotic-associated diabetes come from long-term studies, which show that diabetes, when it occurs, most often does so within the first 6 months on the medication. Little is known about the acute impact of antipsychotic agents on blood glucose levels and clinical outcomes in patients admitted to acute psychiatric units for stays averaging a few weeks. This information gap provided the rationale for Dr. Smiley’s study.

She presented a chart review of 1,212 patients admitted to three acute inpatient psychiatric units in inner-city Atlanta during 2008. The mean age of the patients was 57 years, they had a mean body mass index of 27 kg/m², and the mean daily blood glucose concentration was 122 mg/dL during their stay. Twenty-one percent of the patients had a history of diabetes, and 6% had new hyperglycemia at admission. The most common primary diagnoses on admission were suicidal ideation in 28% of patients, a primary psychotic disorder in 27%, and depression in 16%.

Thirty-seven percent of patients had no prior experience with antipsychotic agents but were newly started on an antipsychotic during their acute inpatient stay. An additional 38% had been on antipsychotic therapy prior to admission and continued on it while hospitalized. Twenty-five percent of patients had never been treated with antipsychotic agents and were not during their hospitalization. Fifty-two percent of patients were treated with atypical antipsychotic agents during their inpatient stay, 17% received both atypical and typical antipsychotics, and 6% got typical antipsychotics only, explained Dr. Smiley, an endocrinologist at Emory University, Atlanta.

She sought answers to three research questions:

• Does prior exposure to antipsychotic therapy affect inpatient blood glucose levels or clinical outcome measures? Mean psychiatric inpatient length of stay was significantly shorter for patients never exposed to antipsychotics, at 9.5 days, compared with 14.2 days in patients who continued on their previous antipsychotic regimen and 13.7 days in antipsychotic-naive patients started on an antipsychotic for the first time. The most likely explanation for the longer stays in patients on antipsychotic therapy was the need to monitor them for side effects, according to Dr. Smiley.

Importantly, mean daily blood glucose concentrations during psychiatric hospitalization did not differ between patients never exposed to antipsychotic agents, those started on an antipsychotic for the first time during their hospitalization, and patients continued on their previous antipsychotics.

• Does the type of antipsychotic agent used during the acute inpatient admission affect blood glucose levels or clinical outcomes?

Mean daily blood glucose levels were similar regardless of whether patients were on atypical antipsychotics, typical antipsychotics, or both. The mean hemoglobin A_1c level was 7.3% in all three groups of antipsychotic-treated patients. However, the rate of medical complications during psychiatric hospitalization was significantly higher among patients on atypical agents, at 23%, compared with 17% in patients on typical antipsychotics and 13% in those on both.

Three percent of patients on atypical antipsychotics-only required transfer to a medical unit for treatment of a complication that arose during psychiatric hospitalization. That was also true for 3% of patients on combined atypical/typical antipsychotic therapy. In contrast, none of the relatively few patients on typical antipsychotics-only required transfer to a medical unit. It’s worth noting that all atypical antipsychotics are not alike in terms of the strength of their association with diabetes. Most antipsychotic-treated patients in this study got olanzapine (Zyprexa) or clozapine (Clozaril). Newer, less diabetogenic atypical agents were less frequently used in this largely indigent population.

• Does a history of diabetes or new hyperglycemia at admission affect outcome measures? Not unexpectedly, patients with a history of diabetes prior to admission had a significantly higher rate of medical complications during their psychiatric inpatient stay: a 28% rate, compared with 22% in patients with no history of diabetes but with hyperglycemia at admission and 20% in patients with neither metabolic abnormality. The most common complication in patients with a history of diabetes was urinary tract infection.

Again unsurprisingly, patients with a history of diabetes had a significantly higher rate of transfer to a medical unit because of medical complications: 5%, compared with no transfers in patients with new hyperglycemia at admission and a 1% transfer rate in patients with neither metabolic abnormality.

Dr. Smiley reported that her research funding came from the National Institutes of Health, Sanofi-Aventis, and Merck.

[email protected]

CHICAGO – Treatment with antipsychotic agents in acute psychiatric inpatient units is not associated with increased blood glucose levels, according to a multicenter study.

"This finding is contrary to what many of us may have previously considered," Dr. Dawn D. Smiley observed in presenting the study findings at the annual scientific sessions of the American Diabetes Association.

A well-recognized association exists between the use of antipsychotic agents and an increased prevalence of diabetes and hyperglycemia, although it remains unclear whether the relationship is causal. The association is especially strong for the atypical or second-generation antipsychotics, which account for more than 90% of all antipsychotic use and are among the top-selling prescription drugs in the United States. Indeed, the Food and Drug Administration has for a decade required the product labeling for all atypical antipsychotics to include a warning about the risks of hyperglycemia and diabetes.

But most data on antipsychotic-associated diabetes come from long-term studies, which show that diabetes, when it occurs, most often does so within the first 6 months on the medication. Little is known about the acute impact of antipsychotic agents on blood glucose levels and clinical outcomes in patients admitted to acute psychiatric units for stays averaging a few weeks. This information gap provided the rationale for Dr. Smiley’s study.

She presented a chart review of 1,212 patients admitted to three acute inpatient psychiatric units in inner-city Atlanta during 2008. The mean age of the patients was 57 years, they had a mean body mass index of 27 kg/m², and the mean daily blood glucose concentration was 122 mg/dL during their stay. Twenty-one percent of the patients had a history of diabetes, and 6% had new hyperglycemia at admission. The most common primary diagnoses on admission were suicidal ideation in 28% of patients, a primary psychotic disorder in 27%, and depression in 16%.

Thirty-seven percent of patients had no prior experience with antipsychotic agents but were newly started on an antipsychotic during their acute inpatient stay. An additional 38% had been on antipsychotic therapy prior to admission and continued on it while hospitalized. Twenty-five percent of patients had never been treated with antipsychotic agents and were not during their hospitalization. Fifty-two percent of patients were treated with atypical antipsychotic agents during their inpatient stay, 17% received both atypical and typical antipsychotics, and 6% got typical antipsychotics only, explained Dr. Smiley, an endocrinologist at Emory University, Atlanta.

She sought answers to three research questions:

• Does prior exposure to antipsychotic therapy affect inpatient blood glucose levels or clinical outcome measures? Mean psychiatric inpatient length of stay was significantly shorter for patients never exposed to antipsychotics, at 9.5 days, compared with 14.2 days in patients who continued on their previous antipsychotic regimen and 13.7 days in antipsychotic-naive patients started on an antipsychotic for the first time. The most likely explanation for the longer stays in patients on antipsychotic therapy was the need to monitor them for side effects, according to Dr. Smiley.

Importantly, mean daily blood glucose concentrations during psychiatric hospitalization did not differ between patients never exposed to antipsychotic agents, those started on an antipsychotic for the first time during their hospitalization, and patients continued on their previous antipsychotics.

• Does the type of antipsychotic agent used during the acute inpatient admission affect blood glucose levels or clinical outcomes?

Mean daily blood glucose levels were similar regardless of whether patients were on atypical antipsychotics, typical antipsychotics, or both. The mean hemoglobin A_1c level was 7.3% in all three groups of antipsychotic-treated patients. However, the rate of medical complications during psychiatric hospitalization was significantly higher among patients on atypical agents, at 23%, compared with 17% in patients on typical antipsychotics and 13% in those on both.

Three percent of patients on atypical antipsychotics-only required transfer to a medical unit for treatment of a complication that arose during psychiatric hospitalization. That was also true for 3% of patients on combined atypical/typical antipsychotic therapy. In contrast, none of the relatively few patients on typical antipsychotics-only required transfer to a medical unit. It’s worth noting that all atypical antipsychotics are not alike in terms of the strength of their association with diabetes. Most antipsychotic-treated patients in this study got olanzapine (Zyprexa) or clozapine (Clozaril). Newer, less diabetogenic atypical agents were less frequently used in this largely indigent population.

• Does a history of diabetes or new hyperglycemia at admission affect outcome measures? Not unexpectedly, patients with a history of diabetes prior to admission had a significantly higher rate of medical complications during their psychiatric inpatient stay: a 28% rate, compared with 22% in patients with no history of diabetes but with hyperglycemia at admission and 20% in patients with neither metabolic abnormality. The most common complication in patients with a history of diabetes was urinary tract infection.

Again unsurprisingly, patients with a history of diabetes had a significantly higher rate of transfer to a medical unit because of medical complications: 5%, compared with no transfers in patients with new hyperglycemia at admission and a 1% transfer rate in patients with neither metabolic abnormality.

Dr. Smiley reported that her research funding came from the National Institutes of Health, Sanofi-Aventis, and Merck.

[email protected]

HOLLYWOOD, FLA. – Lurasidone has hit all of its primary and secondary efficacy endpoints in a phase III clinical trial for the treatment of bipolar I depression.

As a result, the drug, already marketed as Latuda for the treatment of schizophrenia, has been approved by the Food and Drug Administration for a requested expanded indication in treating bipolar I depression. The approval, which came July 1, was made for lurasidone as monotherapy and adjunctive therapy with lithium or valproate.

The phase III PREVAIL 2 (Program to Evaluate the Antidepressant Impact of Lurasidone) study was a 6-week, double-blind, placebo-controlled, multicenter clinical trial involving 505 patients with bipolar I depression. They were randomized to once-daily, flexibly dosed lurasidone at either 20-60 mg/day or 80-120 mg/day, or to placebo.

The primary efficacy endpoint was change from baseline through week 6 in scores on MADRS (the Montgomery-Åsberg Depression Rating Scale). From a mean baseline score of 30, both the lower- and higher-dose lurasidone groups averaged identical 15.4-point reductions, a significantly greater improvement than the 10.7-point decrease in placebo-treated controls, Dr. Antony D. Loebel reported at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

This pattern of closely similar efficacy in the lower- and higher-dose lurasidone groups, whose mean modal doses were 34.9 and 92.3 mg/day, respectively, was repeated for the other study endpoints, observed Dr. Loebel, executive vice president and chief medical officer at Sunovion Pharmaceuticals, Fort Lee, N.J.

For example, the Clinical Global Impression, Bipolar Severity depression score decreased from a baseline of 4.5 by a mean of 1.8 points in the lower-dose lurasidone group and 1.7 points in the higher-dose arm, significantly greater than the 1.1-point decline with placebo.

Similarly, 53% and 51% of the lower- and higher-dose lurasidone groups, respectively, were deemed treatment responders based upon at least a 50% reduction in MADRS scores, compared with 30% of controls.

The remission rate, defined as a final MADRS score of 12 or less, was 42% in the lower-dose lurasidone arm, 40% in patients on higher-dose therapy, and 25% with placebo.

All three patient groups showed similarly modest decreases over time in the Young Mania Rating Scale: a mean 1-point drop in the lower-dose lurasidone arm, a 0.7-point reduction with higher-dose therapy, and a 0.9-point reduction with placebo. That’s an important and reassuring finding, because attempts to treat bipolar mania using conventional antidepressants can result in a switch to mania. In this study, treatment-emergent mania occurred in just 1% of subjects on lower-dose lurasidone, 0% on higher-dose therapy, and 1% on placebo, Dr. Loebel continued.

Numerous other studies have established that roughly 90% of patients with bipolar depression experience severe functional impairment. Of note, PREVAIL 2 patients in the lower-dose lurasidone arm displayed a highly significant mean 9.5-point reduction from a baseline score of 20 on the Sheehan Disability Scale, and the higher-dose lurasidone group showed a 9.8-point decrease. In contrast, scores did not change over time in the control group.

In a similar vein, scores on the Quick Inventory of Depressive Symptomatology-Self-Report improved from a baseline of 33.5 by 19.3 and 19.8 points, respectively, in the lower- and higher-dose lurasidone arms, significantly better than the 12.8-point improvement with placebo, reported Dr. Loebel also of the department of psychiatry at New York University.

A total of 6%-7% of subjects in each study arm discontinued the trial because of adverse events. Nausea and akathisia were the two adverse events that were seen more frequently with lurasidone than placebo. No significant changes in lipids, body weight, or glycemic control were observed.

Lurasidone’s efficacy in bipolar depression is attributed to the drug’s unique pharmacodynamic profile. It is a more potent blocker of the serotonin 5HT7 receptor than are other atypical antipsychotics. It also is a strong antagonist of the dopamine D2 and 5-HT2A receptors, a moderate partial agonist at the 5HT1a receptor, and has a moderate antagonist effect at the alpha-2c receptor.

Before the approval, quetiapine (Seroquel) was the only drug approved as monotherapy for bipolar depression. 

Sunovion Pharmaceuticals sponsored the phase III trial. Dr. Loebel is a company employee.

[email protected]

*This story was updated 7/3/2013.

HOLLYWOOD, FLA. – Lurasidone has hit all of its primary and secondary efficacy endpoints in a phase III clinical trial for the treatment of bipolar I depression.

As a result, the drug, already marketed as Latuda for the treatment of schizophrenia, has been approved by the Food and Drug Administration for a requested expanded indication in treating bipolar I depression. The approval, which came July 1, was made for lurasidone as monotherapy and adjunctive therapy with lithium or valproate.

The phase III PREVAIL 2 (Program to Evaluate the Antidepressant Impact of Lurasidone) study was a 6-week, double-blind, placebo-controlled, multicenter clinical trial involving 505 patients with bipolar I depression. They were randomized to once-daily, flexibly dosed lurasidone at either 20-60 mg/day or 80-120 mg/day, or to placebo.

The primary efficacy endpoint was change from baseline through week 6 in scores on MADRS (the Montgomery-Åsberg Depression Rating Scale). From a mean baseline score of 30, both the lower- and higher-dose lurasidone groups averaged identical 15.4-point reductions, a significantly greater improvement than the 10.7-point decrease in placebo-treated controls, Dr. Antony D. Loebel reported at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

This pattern of closely similar efficacy in the lower- and higher-dose lurasidone groups, whose mean modal doses were 34.9 and 92.3 mg/day, respectively, was repeated for the other study endpoints, observed Dr. Loebel, executive vice president and chief medical officer at Sunovion Pharmaceuticals, Fort Lee, N.J.

For example, the Clinical Global Impression, Bipolar Severity depression score decreased from a baseline of 4.5 by a mean of 1.8 points in the lower-dose lurasidone group and 1.7 points in the higher-dose arm, significantly greater than the 1.1-point decline with placebo.

Similarly, 53% and 51% of the lower- and higher-dose lurasidone groups, respectively, were deemed treatment responders based upon at least a 50% reduction in MADRS scores, compared with 30% of controls.

The remission rate, defined as a final MADRS score of 12 or less, was 42% in the lower-dose lurasidone arm, 40% in patients on higher-dose therapy, and 25% with placebo.

All three patient groups showed similarly modest decreases over time in the Young Mania Rating Scale: a mean 1-point drop in the lower-dose lurasidone arm, a 0.7-point reduction with higher-dose therapy, and a 0.9-point reduction with placebo. That’s an important and reassuring finding, because attempts to treat bipolar mania using conventional antidepressants can result in a switch to mania. In this study, treatment-emergent mania occurred in just 1% of subjects on lower-dose lurasidone, 0% on higher-dose therapy, and 1% on placebo, Dr. Loebel continued.

Numerous other studies have established that roughly 90% of patients with bipolar depression experience severe functional impairment. Of note, PREVAIL 2 patients in the lower-dose lurasidone arm displayed a highly significant mean 9.5-point reduction from a baseline score of 20 on the Sheehan Disability Scale, and the higher-dose lurasidone group showed a 9.8-point decrease. In contrast, scores did not change over time in the control group.

In a similar vein, scores on the Quick Inventory of Depressive Symptomatology-Self-Report improved from a baseline of 33.5 by 19.3 and 19.8 points, respectively, in the lower- and higher-dose lurasidone arms, significantly better than the 12.8-point improvement with placebo, reported Dr. Loebel also of the department of psychiatry at New York University.

A total of 6%-7% of subjects in each study arm discontinued the trial because of adverse events. Nausea and akathisia were the two adverse events that were seen more frequently with lurasidone than placebo. No significant changes in lipids, body weight, or glycemic control were observed.

Lurasidone’s efficacy in bipolar depression is attributed to the drug’s unique pharmacodynamic profile. It is a more potent blocker of the serotonin 5HT7 receptor than are other atypical antipsychotics. It also is a strong antagonist of the dopamine D2 and 5-HT2A receptors, a moderate partial agonist at the 5HT1a receptor, and has a moderate antagonist effect at the alpha-2c receptor.

Before the approval, quetiapine (Seroquel) was the only drug approved as monotherapy for bipolar depression. 

Sunovion Pharmaceuticals sponsored the phase III trial. Dr. Loebel is a company employee.

[email protected]

*This story was updated 7/3/2013.

HOLLYWOOD, FLA. – Lurasidone has hit all of its primary and secondary efficacy endpoints in a phase III clinical trial for the treatment of bipolar I depression.

As a result, the drug, already marketed as Latuda for the treatment of schizophrenia, has been approved by the Food and Drug Administration for a requested expanded indication in treating bipolar I depression. The approval, which came July 1, was made for lurasidone as monotherapy and adjunctive therapy with lithium or valproate.

The phase III PREVAIL 2 (Program to Evaluate the Antidepressant Impact of Lurasidone) study was a 6-week, double-blind, placebo-controlled, multicenter clinical trial involving 505 patients with bipolar I depression. They were randomized to once-daily, flexibly dosed lurasidone at either 20-60 mg/day or 80-120 mg/day, or to placebo.

The primary efficacy endpoint was change from baseline through week 6 in scores on MADRS (the Montgomery-Åsberg Depression Rating Scale). From a mean baseline score of 30, both the lower- and higher-dose lurasidone groups averaged identical 15.4-point reductions, a significantly greater improvement than the 10.7-point decrease in placebo-treated controls, Dr. Antony D. Loebel reported at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

This pattern of closely similar efficacy in the lower- and higher-dose lurasidone groups, whose mean modal doses were 34.9 and 92.3 mg/day, respectively, was repeated for the other study endpoints, observed Dr. Loebel, executive vice president and chief medical officer at Sunovion Pharmaceuticals, Fort Lee, N.J.

For example, the Clinical Global Impression, Bipolar Severity depression score decreased from a baseline of 4.5 by a mean of 1.8 points in the lower-dose lurasidone group and 1.7 points in the higher-dose arm, significantly greater than the 1.1-point decline with placebo.

Similarly, 53% and 51% of the lower- and higher-dose lurasidone groups, respectively, were deemed treatment responders based upon at least a 50% reduction in MADRS scores, compared with 30% of controls.

The remission rate, defined as a final MADRS score of 12 or less, was 42% in the lower-dose lurasidone arm, 40% in patients on higher-dose therapy, and 25% with placebo.

All three patient groups showed similarly modest decreases over time in the Young Mania Rating Scale: a mean 1-point drop in the lower-dose lurasidone arm, a 0.7-point reduction with higher-dose therapy, and a 0.9-point reduction with placebo. That’s an important and reassuring finding, because attempts to treat bipolar mania using conventional antidepressants can result in a switch to mania. In this study, treatment-emergent mania occurred in just 1% of subjects on lower-dose lurasidone, 0% on higher-dose therapy, and 1% on placebo, Dr. Loebel continued.

Numerous other studies have established that roughly 90% of patients with bipolar depression experience severe functional impairment. Of note, PREVAIL 2 patients in the lower-dose lurasidone arm displayed a highly significant mean 9.5-point reduction from a baseline score of 20 on the Sheehan Disability Scale, and the higher-dose lurasidone group showed a 9.8-point decrease. In contrast, scores did not change over time in the control group.

In a similar vein, scores on the Quick Inventory of Depressive Symptomatology-Self-Report improved from a baseline of 33.5 by 19.3 and 19.8 points, respectively, in the lower- and higher-dose lurasidone arms, significantly better than the 12.8-point improvement with placebo, reported Dr. Loebel also of the department of psychiatry at New York University.

A total of 6%-7% of subjects in each study arm discontinued the trial because of adverse events. Nausea and akathisia were the two adverse events that were seen more frequently with lurasidone than placebo. No significant changes in lipids, body weight, or glycemic control were observed.

Lurasidone’s efficacy in bipolar depression is attributed to the drug’s unique pharmacodynamic profile. It is a more potent blocker of the serotonin 5HT7 receptor than are other atypical antipsychotics. It also is a strong antagonist of the dopamine D2 and 5-HT2A receptors, a moderate partial agonist at the 5HT1a receptor, and has a moderate antagonist effect at the alpha-2c receptor.

Before the approval, quetiapine (Seroquel) was the only drug approved as monotherapy for bipolar depression. 

Sunovion Pharmaceuticals sponsored the phase III trial. Dr. Loebel is a company employee.

[email protected]

*This story was updated 7/3/2013.

SAN FRANCISCO – Thirty-seven percent of 175 hospitalized adolescents diagnosed with bipolar disorder met criteria for a new disorder listed in the DSM-5 – disruptive mood dysregulation disorder.

Nearly all of the patients (96%) had been diagnosed with bipolar I disorder "not otherwise specified" (NOS) at the time of admission, a retrospective study found. Three other bipolar diagnoses were applied to two patients each: bipolar depression, bipolar mania, or mixed-episode bipolar disorder, David L. Pogge, Ph.D., reported at the annual meeting of the American Psychiatric Association.

The findings suggest that a substantial proportion of adolescent inpatients diagnosed with bipolar disorder may instead meet criteria for disruptive mood dysregulation disorder, and that clinicians should be more careful in diagnosing bipolar disorder, especially bipolar NOS, said Dr. Pogge of the department of psychology and counseling at Fairleigh Dickinson University, Teaneck, N.J. He also serves as director of psychology at Four Winds Hospital, which operates four campuses in New York state.

The study included records for all 1,505 patients aged 13-17 years who were admitted to a private psychiatric hospital over a 2-year period. At the time of admission, clinicians rated 1,351 patients as having at least moderate depression and 368 as also having severe symptoms of hostility and explosiveness. They diagnosed bipolar disorder in 259 cases. The investigators analyzed records for 174 patients with complete records or who had at least moderate depression and severe symptoms of hostility and explosiveness but no signs of elation or euphoria at the time of admission.

Disruptive mood dysregulation disorder is marked by intense temper outbursts superimposed on a background of persistent depressed or irritable mood. Temper outbursts and aggression are common reasons for inpatient admissions of children and adolescents, Dr. Pogge noted in his poster presentation.

Compared with the 63% of patients who did not meet criteria for disruptive mood dysregulation disorder (DMDD), patients who met the DMDD criteria were significantly more likely to experience restraint or seclusion while hospitalized (30% vs. 20%), receive a significantly higher number of restraints or seclusions (2.2 vs. 0.8), and remain hospitalized significantly longer (25 days vs. 21 days), he reported. At the time of discharge, clinicians’ ratings on the Global Assessment of Functioning (GAF) scale indicated significantly greater global psychopathology in patients with DMDD (a mean GAF score of 44), compared with patients who did not meet DMDD criteria (a mean GAF score of 50).

The two groups did not differ significantly by age, clinician ratings of depression severity, or clinical ratings of global psychopathology at admission.

The study identified a subgroup of adolescent inpatients diagnosed with bipolar disorder without euphoric symptoms who exhibited explosiveness, hostility, and concurrent depression, comprising roughly a third of bipolar disorder diagnoses in the cohort. The findings suggest that these patients who lack signs of elevated mood and meet DMDD criteria routinely get diagnosed with bipolar I disorder, have a more problematic hospital stay, and have more symptoms at discharge, Dr. Pogge and his coinvestigators concluded.

The bipolar diagnoses might be incorrect, or there might be a substantial rate of comorbidity between DMDD and bipolar disease, he said.

The results also suggest that DMDD might be a common reason for psychiatric hospitalization of adolescents.

The study excluded patients whose records suggested other confounding factors or were missing any data on outcome measures.

Dr. Pogge reported having no relevant financial disclosures.

[email protected]

On Twitter @sherryboschert

SAN FRANCISCO – Thirty-seven percent of 175 hospitalized adolescents diagnosed with bipolar disorder met criteria for a new disorder listed in the DSM-5 – disruptive mood dysregulation disorder.

Nearly all of the patients (96%) had been diagnosed with bipolar I disorder "not otherwise specified" (NOS) at the time of admission, a retrospective study found. Three other bipolar diagnoses were applied to two patients each: bipolar depression, bipolar mania, or mixed-episode bipolar disorder, David L. Pogge, Ph.D., reported at the annual meeting of the American Psychiatric Association.

The findings suggest that a substantial proportion of adolescent inpatients diagnosed with bipolar disorder may instead meet criteria for disruptive mood dysregulation disorder, and that clinicians should be more careful in diagnosing bipolar disorder, especially bipolar NOS, said Dr. Pogge of the department of psychology and counseling at Fairleigh Dickinson University, Teaneck, N.J. He also serves as director of psychology at Four Winds Hospital, which operates four campuses in New York state.

The study included records for all 1,505 patients aged 13-17 years who were admitted to a private psychiatric hospital over a 2-year period. At the time of admission, clinicians rated 1,351 patients as having at least moderate depression and 368 as also having severe symptoms of hostility and explosiveness. They diagnosed bipolar disorder in 259 cases. The investigators analyzed records for 174 patients with complete records or who had at least moderate depression and severe symptoms of hostility and explosiveness but no signs of elation or euphoria at the time of admission.

Disruptive mood dysregulation disorder is marked by intense temper outbursts superimposed on a background of persistent depressed or irritable mood. Temper outbursts and aggression are common reasons for inpatient admissions of children and adolescents, Dr. Pogge noted in his poster presentation.

Compared with the 63% of patients who did not meet criteria for disruptive mood dysregulation disorder (DMDD), patients who met the DMDD criteria were significantly more likely to experience restraint or seclusion while hospitalized (30% vs. 20%), receive a significantly higher number of restraints or seclusions (2.2 vs. 0.8), and remain hospitalized significantly longer (25 days vs. 21 days), he reported. At the time of discharge, clinicians’ ratings on the Global Assessment of Functioning (GAF) scale indicated significantly greater global psychopathology in patients with DMDD (a mean GAF score of 44), compared with patients who did not meet DMDD criteria (a mean GAF score of 50).

The two groups did not differ significantly by age, clinician ratings of depression severity, or clinical ratings of global psychopathology at admission.

The study identified a subgroup of adolescent inpatients diagnosed with bipolar disorder without euphoric symptoms who exhibited explosiveness, hostility, and concurrent depression, comprising roughly a third of bipolar disorder diagnoses in the cohort. The findings suggest that these patients who lack signs of elevated mood and meet DMDD criteria routinely get diagnosed with bipolar I disorder, have a more problematic hospital stay, and have more symptoms at discharge, Dr. Pogge and his coinvestigators concluded.

The bipolar diagnoses might be incorrect, or there might be a substantial rate of comorbidity between DMDD and bipolar disease, he said.

The results also suggest that DMDD might be a common reason for psychiatric hospitalization of adolescents.

The study excluded patients whose records suggested other confounding factors or were missing any data on outcome measures.

Dr. Pogge reported having no relevant financial disclosures.

[email protected]

On Twitter @sherryboschert

SAN FRANCISCO – Thirty-seven percent of 175 hospitalized adolescents diagnosed with bipolar disorder met criteria for a new disorder listed in the DSM-5 – disruptive mood dysregulation disorder.

Nearly all of the patients (96%) had been diagnosed with bipolar I disorder "not otherwise specified" (NOS) at the time of admission, a retrospective study found. Three other bipolar diagnoses were applied to two patients each: bipolar depression, bipolar mania, or mixed-episode bipolar disorder, David L. Pogge, Ph.D., reported at the annual meeting of the American Psychiatric Association.

The findings suggest that a substantial proportion of adolescent inpatients diagnosed with bipolar disorder may instead meet criteria for disruptive mood dysregulation disorder, and that clinicians should be more careful in diagnosing bipolar disorder, especially bipolar NOS, said Dr. Pogge of the department of psychology and counseling at Fairleigh Dickinson University, Teaneck, N.J. He also serves as director of psychology at Four Winds Hospital, which operates four campuses in New York state.

The study included records for all 1,505 patients aged 13-17 years who were admitted to a private psychiatric hospital over a 2-year period. At the time of admission, clinicians rated 1,351 patients as having at least moderate depression and 368 as also having severe symptoms of hostility and explosiveness. They diagnosed bipolar disorder in 259 cases. The investigators analyzed records for 174 patients with complete records or who had at least moderate depression and severe symptoms of hostility and explosiveness but no signs of elation or euphoria at the time of admission.

Disruptive mood dysregulation disorder is marked by intense temper outbursts superimposed on a background of persistent depressed or irritable mood. Temper outbursts and aggression are common reasons for inpatient admissions of children and adolescents, Dr. Pogge noted in his poster presentation.

Compared with the 63% of patients who did not meet criteria for disruptive mood dysregulation disorder (DMDD), patients who met the DMDD criteria were significantly more likely to experience restraint or seclusion while hospitalized (30% vs. 20%), receive a significantly higher number of restraints or seclusions (2.2 vs. 0.8), and remain hospitalized significantly longer (25 days vs. 21 days), he reported. At the time of discharge, clinicians’ ratings on the Global Assessment of Functioning (GAF) scale indicated significantly greater global psychopathology in patients with DMDD (a mean GAF score of 44), compared with patients who did not meet DMDD criteria (a mean GAF score of 50).

The two groups did not differ significantly by age, clinician ratings of depression severity, or clinical ratings of global psychopathology at admission.

The study identified a subgroup of adolescent inpatients diagnosed with bipolar disorder without euphoric symptoms who exhibited explosiveness, hostility, and concurrent depression, comprising roughly a third of bipolar disorder diagnoses in the cohort. The findings suggest that these patients who lack signs of elevated mood and meet DMDD criteria routinely get diagnosed with bipolar I disorder, have a more problematic hospital stay, and have more symptoms at discharge, Dr. Pogge and his coinvestigators concluded.

The bipolar diagnoses might be incorrect, or there might be a substantial rate of comorbidity between DMDD and bipolar disease, he said.

The results also suggest that DMDD might be a common reason for psychiatric hospitalization of adolescents.

The study excluded patients whose records suggested other confounding factors or were missing any data on outcome measures.

Dr. Pogge reported having no relevant financial disclosures.

[email protected]

On Twitter @sherryboschert

HOLLYWOOD, FLA. – Transcranial magnetic stimulation shows promise in highly treatment-resistant bipolar depression, a small observational study suggested.

Most studies of transcranial magnetic stimulation (TMS) have focused on treatment of major depressive disorder, the indication for which this noninvasive device therapy has Food and Drug Administration approval. TMS also is under study for the treatment of headaches, as well as for improvement of the negative symptoms of schizophrenia.

Yet little work has been done on TMS for bipolar depression, even though a pressing need exists for new treatment options for this often highly disruptive mood disorder. Antidepressant medications are often ineffective or can trigger a switch to a manic or hypomanic episode, Dr. William S. Gilmer noted at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

He reported on 10 patients with bipolar II disorder and 4 who met criteria for bipolar disorder not otherwise specified. All had complicated nonpsychotic depression. All were refractory to and/or intolerant of multiple antidepressant agents during their current episode; indeed, the patients had previously been on a mean of 6.4 antidepressant drugs during this episode, which had already lasted more than 18 months in 9 of 14 cases. Four patients were previous nonresponders to ECT. None of the subjects had bipolar activation symptoms such as grandiosity, nocturnal alertness, or agitation at baseline, according to Dr. Gilmer, associate professor of clinical psychiatry and behavioral sciences at Northwestern University, Chicago.

After an extended period during which he attempted to optimize the participants’ medications, including reducing benzodiazepines and increasing mood-stabilizing drugs if necessary, all patients underwent high-frequency TMS at 10-Hz over the left dorsolateral prefrontal cortex 5 days per week according to the standard procedure using the NeuroStar device marketed by Neuronetics.

Nine of 14 patients achieved a clinically meaningful antidepressant response to TMS, as defined by at least a 50% reduction in scores on the Quick Inventory of Depressive Symptomatology (QIDS-16 SR) from an initial mean baseline of 18.9. A mean of 24.6 sessions was required. Four patients achieved and maintained remission, as defined by a QIDS-16 SR score below 6; this required a mean of 24.8 TMS sessions, followed by a taper phase.

Two of the four previous nonresponders to ECT achieved full remission on TMS, and a third had a significant response.

Although there were no study dropouts, seven patients experienced bipolar activation symptoms during TMS therapy that required drug therapy. Of note, four of five TMS nonresponders experienced clinically significant activation symptoms, compared with just three of nine TMS responders. Thus, the emergence of activation symptoms during TMS may turn out to be a predictor of poor outcome. This is a possibility warranting further study in controlled trials aimed at establishing optimal TMS treatment parameters in bipolar depression, the psychiatrist suggested.

Dr. Gilmer is on the speakers’ bureau for Neuronetics.

[email protected]

HOLLYWOOD, FLA. – Transcranial magnetic stimulation shows promise in highly treatment-resistant bipolar depression, a small observational study suggested.

Most studies of transcranial magnetic stimulation (TMS) have focused on treatment of major depressive disorder, the indication for which this noninvasive device therapy has Food and Drug Administration approval. TMS also is under study for the treatment of headaches, as well as for improvement of the negative symptoms of schizophrenia.

Yet little work has been done on TMS for bipolar depression, even though a pressing need exists for new treatment options for this often highly disruptive mood disorder. Antidepressant medications are often ineffective or can trigger a switch to a manic or hypomanic episode, Dr. William S. Gilmer noted at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

He reported on 10 patients with bipolar II disorder and 4 who met criteria for bipolar disorder not otherwise specified. All had complicated nonpsychotic depression. All were refractory to and/or intolerant of multiple antidepressant agents during their current episode; indeed, the patients had previously been on a mean of 6.4 antidepressant drugs during this episode, which had already lasted more than 18 months in 9 of 14 cases. Four patients were previous nonresponders to ECT. None of the subjects had bipolar activation symptoms such as grandiosity, nocturnal alertness, or agitation at baseline, according to Dr. Gilmer, associate professor of clinical psychiatry and behavioral sciences at Northwestern University, Chicago.

After an extended period during which he attempted to optimize the participants’ medications, including reducing benzodiazepines and increasing mood-stabilizing drugs if necessary, all patients underwent high-frequency TMS at 10-Hz over the left dorsolateral prefrontal cortex 5 days per week according to the standard procedure using the NeuroStar device marketed by Neuronetics.

Nine of 14 patients achieved a clinically meaningful antidepressant response to TMS, as defined by at least a 50% reduction in scores on the Quick Inventory of Depressive Symptomatology (QIDS-16 SR) from an initial mean baseline of 18.9. A mean of 24.6 sessions was required. Four patients achieved and maintained remission, as defined by a QIDS-16 SR score below 6; this required a mean of 24.8 TMS sessions, followed by a taper phase.

Two of the four previous nonresponders to ECT achieved full remission on TMS, and a third had a significant response.

Although there were no study dropouts, seven patients experienced bipolar activation symptoms during TMS therapy that required drug therapy. Of note, four of five TMS nonresponders experienced clinically significant activation symptoms, compared with just three of nine TMS responders. Thus, the emergence of activation symptoms during TMS may turn out to be a predictor of poor outcome. This is a possibility warranting further study in controlled trials aimed at establishing optimal TMS treatment parameters in bipolar depression, the psychiatrist suggested.

Dr. Gilmer is on the speakers’ bureau for Neuronetics.

[email protected]

HOLLYWOOD, FLA. – Transcranial magnetic stimulation shows promise in highly treatment-resistant bipolar depression, a small observational study suggested.

Most studies of transcranial magnetic stimulation (TMS) have focused on treatment of major depressive disorder, the indication for which this noninvasive device therapy has Food and Drug Administration approval. TMS also is under study for the treatment of headaches, as well as for improvement of the negative symptoms of schizophrenia.

Yet little work has been done on TMS for bipolar depression, even though a pressing need exists for new treatment options for this often highly disruptive mood disorder. Antidepressant medications are often ineffective or can trigger a switch to a manic or hypomanic episode, Dr. William S. Gilmer noted at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

He reported on 10 patients with bipolar II disorder and 4 who met criteria for bipolar disorder not otherwise specified. All had complicated nonpsychotic depression. All were refractory to and/or intolerant of multiple antidepressant agents during their current episode; indeed, the patients had previously been on a mean of 6.4 antidepressant drugs during this episode, which had already lasted more than 18 months in 9 of 14 cases. Four patients were previous nonresponders to ECT. None of the subjects had bipolar activation symptoms such as grandiosity, nocturnal alertness, or agitation at baseline, according to Dr. Gilmer, associate professor of clinical psychiatry and behavioral sciences at Northwestern University, Chicago.

After an extended period during which he attempted to optimize the participants’ medications, including reducing benzodiazepines and increasing mood-stabilizing drugs if necessary, all patients underwent high-frequency TMS at 10-Hz over the left dorsolateral prefrontal cortex 5 days per week according to the standard procedure using the NeuroStar device marketed by Neuronetics.

Nine of 14 patients achieved a clinically meaningful antidepressant response to TMS, as defined by at least a 50% reduction in scores on the Quick Inventory of Depressive Symptomatology (QIDS-16 SR) from an initial mean baseline of 18.9. A mean of 24.6 sessions was required. Four patients achieved and maintained remission, as defined by a QIDS-16 SR score below 6; this required a mean of 24.8 TMS sessions, followed by a taper phase.

Two of the four previous nonresponders to ECT achieved full remission on TMS, and a third had a significant response.

Although there were no study dropouts, seven patients experienced bipolar activation symptoms during TMS therapy that required drug therapy. Of note, four of five TMS nonresponders experienced clinically significant activation symptoms, compared with just three of nine TMS responders. Thus, the emergence of activation symptoms during TMS may turn out to be a predictor of poor outcome. This is a possibility warranting further study in controlled trials aimed at establishing optimal TMS treatment parameters in bipolar depression, the psychiatrist suggested.

Dr. Gilmer is on the speakers’ bureau for Neuronetics.

[email protected]

HOLLYWOOD, FLA. – A 4-month course of the oral antiviral agent valacyclovir boosted cognition in herpes simplex virus-1–seropositive patients with bipolar disorder and cognitive impairment in a randomized, double-blind placebo-controlled clinical trial.

In this 60-patient study, 53% of participants assigned to valacyclovir (Valtrex) exhibited a clinically meaningful improvement in cognitive function, defined as at least a 10-point gain over baseline on the Repeatable Battery for the Assessment of Neurological Status (RBANS), compared with 14% in the placebo arm, Dr. Jennifer L. Payne reported at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

The impressive improvement in response to valacyclovir documented in this study lends support to the viral hypothesis of mental illness, she said. This hypothesis posits that infection with one of the herpes viruses can in genetically vulnerable individuals lead to major mental illness, including schizophrenia, bipolar disorder, and perhaps Alzheimer’s disease.

"The idea behind this is that episodic reactivation of the virus in the [central nervous system] by stress or other stimuli could trigger mood, cognitive, or psychotic symptoms. If you treat patients you see this all the time: A patient comes under some kind of stress and becomes psychiatrically ill. One of the thoughts is that [herpes simplex virus] could underlie some of that psychopathology," according to Dr. Payne, a psychiatrist and director of the women’s mood disorders center at Johns Hopkins University, Baltimore.

She credited Faith B. Dickerson, Ph.D., of the Sheppard Pratt Institute in Baltimore with earlier groundbreaking work identifying a link between herpes simplex virus type 1 (HSV-1) and cognitive dysfunction in bipolar disorder. Dr. Dickerson and her colleagues reported a roughly 20-fold increased risk for cognitive impairment on the RBANS in HSV-1–seropositive, compared with seronegative patients with bipolar disorder (Biol. Psychiatry 2004;55:588-93).

The RBANS is a paper and pencil test that takes roughly 25 minutes. The mean score in the general population is 100. One standard deviation below the mean is a score of 85. Upon retaking the test, 16% of the general population are able to improve their score by 10 points or more, a rate close to the placebo group’s performance in Dr. Payne’s bipolar disorder study. The RBANS has individual sections for attention, immediate memory, delayed memory, language, and visuospatial construction.

HSV-1 typically causes oral herpes lesions. It’s an extremely common infection. By middle age, roughly 70% of Americans have serologic antibody titers to HSV-1. The virus infects the CNS and often remains in a latent state for many years, punctuated by symptomatic recurrences.

Dr. Payne screened 106 bipolar disorder patients; 84 proved HSV-1 seropositive. The mean baseline RBANS score in the seropositive patients was 75, compared with 92 in the seronegative cohort. The observed association between HSV-1 serologic status and RBANS score remained significant in a multivariate logistic regression analysis after investigators controlled for education level.

The 60 study participants were bipolar disorder outpatients, with an average age of 43. Thirty-seven percent met diagnostic criteria for bipolar I disorder; the rest, for bipolar II disorder. All were required to have baseline cognitive impairment as reflected by an RBANS score of 85 or less. Their average baseline Montgomery-Asberg Depression Rating Scale (MADRS) score was 24, with a Young Mania Rating Scale (YMRS) score of 8. Patients remained on their usual psychiatric medications during the study.

Participants in the 4-month trial were evaluated every 2 weeks for a change in mood symptoms using the MADRS and YMRS. The results came as a surprise.

"Our hypothesis had been that cognitive improvement with valacyclovir would be associated with improvement in depression, but the MADRS scores didn’t change over time," according to Dr. Payne.

As is typical in months-long clinical trials conducted in patients with bipolar disorder, there was a high dropout rate. Mean RBANS scores in the 19 patients in the valacyclovir group who completed the study improved from a baseline of 67.6 to 77.7 at 4 months. The 22 study completers in the control group showed no significant change in scores over time.

Dr. Payne said that if these results are confirmed in another clinical trial – and she plans to conduct one including seropositive bipolar disorder patients who are not cognitively impaired – it would be practice changing.

"If these findings hold up, it would indicate that as clinicians, we need to be testing for HSV-1 and treating it in our patients," she said.

Her future plans also include studying HSV-1 antibody status, cognition, and the possible impact of antiviral therapy in patients with major depressive disorder.

Patients with bipolar disorder often complain and exhibit symptoms of cognitive dysfunction, particularly in the domains of attention, memory, and executive function. The dysfunction typically worsens during manic or depressive episodes, but it’s often still present when bipolar disorder patients are affectively neutral.

The randomized trial was funded by the Stanley Medical Research Institute. Dr. Payne reported serving as a consultant to Pfizer and AstraZeneca.

[email protected]

HOLLYWOOD, FLA. – A 4-month course of the oral antiviral agent valacyclovir boosted cognition in herpes simplex virus-1–seropositive patients with bipolar disorder and cognitive impairment in a randomized, double-blind placebo-controlled clinical trial.

In this 60-patient study, 53% of participants assigned to valacyclovir (Valtrex) exhibited a clinically meaningful improvement in cognitive function, defined as at least a 10-point gain over baseline on the Repeatable Battery for the Assessment of Neurological Status (RBANS), compared with 14% in the placebo arm, Dr. Jennifer L. Payne reported at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

The impressive improvement in response to valacyclovir documented in this study lends support to the viral hypothesis of mental illness, she said. This hypothesis posits that infection with one of the herpes viruses can in genetically vulnerable individuals lead to major mental illness, including schizophrenia, bipolar disorder, and perhaps Alzheimer’s disease.

"The idea behind this is that episodic reactivation of the virus in the [central nervous system] by stress or other stimuli could trigger mood, cognitive, or psychotic symptoms. If you treat patients you see this all the time: A patient comes under some kind of stress and becomes psychiatrically ill. One of the thoughts is that [herpes simplex virus] could underlie some of that psychopathology," according to Dr. Payne, a psychiatrist and director of the women’s mood disorders center at Johns Hopkins University, Baltimore.

She credited Faith B. Dickerson, Ph.D., of the Sheppard Pratt Institute in Baltimore with earlier groundbreaking work identifying a link between herpes simplex virus type 1 (HSV-1) and cognitive dysfunction in bipolar disorder. Dr. Dickerson and her colleagues reported a roughly 20-fold increased risk for cognitive impairment on the RBANS in HSV-1–seropositive, compared with seronegative patients with bipolar disorder (Biol. Psychiatry 2004;55:588-93).

The RBANS is a paper and pencil test that takes roughly 25 minutes. The mean score in the general population is 100. One standard deviation below the mean is a score of 85. Upon retaking the test, 16% of the general population are able to improve their score by 10 points or more, a rate close to the placebo group’s performance in Dr. Payne’s bipolar disorder study. The RBANS has individual sections for attention, immediate memory, delayed memory, language, and visuospatial construction.

HSV-1 typically causes oral herpes lesions. It’s an extremely common infection. By middle age, roughly 70% of Americans have serologic antibody titers to HSV-1. The virus infects the CNS and often remains in a latent state for many years, punctuated by symptomatic recurrences.

Dr. Payne screened 106 bipolar disorder patients; 84 proved HSV-1 seropositive. The mean baseline RBANS score in the seropositive patients was 75, compared with 92 in the seronegative cohort. The observed association between HSV-1 serologic status and RBANS score remained significant in a multivariate logistic regression analysis after investigators controlled for education level.

The 60 study participants were bipolar disorder outpatients, with an average age of 43. Thirty-seven percent met diagnostic criteria for bipolar I disorder; the rest, for bipolar II disorder. All were required to have baseline cognitive impairment as reflected by an RBANS score of 85 or less. Their average baseline Montgomery-Asberg Depression Rating Scale (MADRS) score was 24, with a Young Mania Rating Scale (YMRS) score of 8. Patients remained on their usual psychiatric medications during the study.

Participants in the 4-month trial were evaluated every 2 weeks for a change in mood symptoms using the MADRS and YMRS. The results came as a surprise.

"Our hypothesis had been that cognitive improvement with valacyclovir would be associated with improvement in depression, but the MADRS scores didn’t change over time," according to Dr. Payne.

As is typical in months-long clinical trials conducted in patients with bipolar disorder, there was a high dropout rate. Mean RBANS scores in the 19 patients in the valacyclovir group who completed the study improved from a baseline of 67.6 to 77.7 at 4 months. The 22 study completers in the control group showed no significant change in scores over time.

Dr. Payne said that if these results are confirmed in another clinical trial – and she plans to conduct one including seropositive bipolar disorder patients who are not cognitively impaired – it would be practice changing.

"If these findings hold up, it would indicate that as clinicians, we need to be testing for HSV-1 and treating it in our patients," she said.

Her future plans also include studying HSV-1 antibody status, cognition, and the possible impact of antiviral therapy in patients with major depressive disorder.

Patients with bipolar disorder often complain and exhibit symptoms of cognitive dysfunction, particularly in the domains of attention, memory, and executive function. The dysfunction typically worsens during manic or depressive episodes, but it’s often still present when bipolar disorder patients are affectively neutral.

The randomized trial was funded by the Stanley Medical Research Institute. Dr. Payne reported serving as a consultant to Pfizer and AstraZeneca.

[email protected]

HOLLYWOOD, FLA. – A 4-month course of the oral antiviral agent valacyclovir boosted cognition in herpes simplex virus-1–seropositive patients with bipolar disorder and cognitive impairment in a randomized, double-blind placebo-controlled clinical trial.

In this 60-patient study, 53% of participants assigned to valacyclovir (Valtrex) exhibited a clinically meaningful improvement in cognitive function, defined as at least a 10-point gain over baseline on the Repeatable Battery for the Assessment of Neurological Status (RBANS), compared with 14% in the placebo arm, Dr. Jennifer L. Payne reported at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

The impressive improvement in response to valacyclovir documented in this study lends support to the viral hypothesis of mental illness, she said. This hypothesis posits that infection with one of the herpes viruses can in genetically vulnerable individuals lead to major mental illness, including schizophrenia, bipolar disorder, and perhaps Alzheimer’s disease.

"The idea behind this is that episodic reactivation of the virus in the [central nervous system] by stress or other stimuli could trigger mood, cognitive, or psychotic symptoms. If you treat patients you see this all the time: A patient comes under some kind of stress and becomes psychiatrically ill. One of the thoughts is that [herpes simplex virus] could underlie some of that psychopathology," according to Dr. Payne, a psychiatrist and director of the women’s mood disorders center at Johns Hopkins University, Baltimore.

She credited Faith B. Dickerson, Ph.D., of the Sheppard Pratt Institute in Baltimore with earlier groundbreaking work identifying a link between herpes simplex virus type 1 (HSV-1) and cognitive dysfunction in bipolar disorder. Dr. Dickerson and her colleagues reported a roughly 20-fold increased risk for cognitive impairment on the RBANS in HSV-1–seropositive, compared with seronegative patients with bipolar disorder (Biol. Psychiatry 2004;55:588-93).

The RBANS is a paper and pencil test that takes roughly 25 minutes. The mean score in the general population is 100. One standard deviation below the mean is a score of 85. Upon retaking the test, 16% of the general population are able to improve their score by 10 points or more, a rate close to the placebo group’s performance in Dr. Payne’s bipolar disorder study. The RBANS has individual sections for attention, immediate memory, delayed memory, language, and visuospatial construction.

HSV-1 typically causes oral herpes lesions. It’s an extremely common infection. By middle age, roughly 70% of Americans have serologic antibody titers to HSV-1. The virus infects the CNS and often remains in a latent state for many years, punctuated by symptomatic recurrences.

Dr. Payne screened 106 bipolar disorder patients; 84 proved HSV-1 seropositive. The mean baseline RBANS score in the seropositive patients was 75, compared with 92 in the seronegative cohort. The observed association between HSV-1 serologic status and RBANS score remained significant in a multivariate logistic regression analysis after investigators controlled for education level.

The 60 study participants were bipolar disorder outpatients, with an average age of 43. Thirty-seven percent met diagnostic criteria for bipolar I disorder; the rest, for bipolar II disorder. All were required to have baseline cognitive impairment as reflected by an RBANS score of 85 or less. Their average baseline Montgomery-Asberg Depression Rating Scale (MADRS) score was 24, with a Young Mania Rating Scale (YMRS) score of 8. Patients remained on their usual psychiatric medications during the study.

Participants in the 4-month trial were evaluated every 2 weeks for a change in mood symptoms using the MADRS and YMRS. The results came as a surprise.

"Our hypothesis had been that cognitive improvement with valacyclovir would be associated with improvement in depression, but the MADRS scores didn’t change over time," according to Dr. Payne.

As is typical in months-long clinical trials conducted in patients with bipolar disorder, there was a high dropout rate. Mean RBANS scores in the 19 patients in the valacyclovir group who completed the study improved from a baseline of 67.6 to 77.7 at 4 months. The 22 study completers in the control group showed no significant change in scores over time.

Dr. Payne said that if these results are confirmed in another clinical trial – and she plans to conduct one including seropositive bipolar disorder patients who are not cognitively impaired – it would be practice changing.

"If these findings hold up, it would indicate that as clinicians, we need to be testing for HSV-1 and treating it in our patients," she said.

Her future plans also include studying HSV-1 antibody status, cognition, and the possible impact of antiviral therapy in patients with major depressive disorder.

Patients with bipolar disorder often complain and exhibit symptoms of cognitive dysfunction, particularly in the domains of attention, memory, and executive function. The dysfunction typically worsens during manic or depressive episodes, but it’s often still present when bipolar disorder patients are affectively neutral.

The randomized trial was funded by the Stanley Medical Research Institute. Dr. Payne reported serving as a consultant to Pfizer and AstraZeneca.

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