The Bipolar-AD(H)D Connection
Results of a MEDLINE Search by Ivan Goldberg, M.D.
Psychopharmacol Bull. 2008;41(4):37-47.
Frequency of stimulant treatment and of stimulant-associated mania/hypomania in
bipolar disorder patients.
Wingo AP, Ghaemi SN.
Bipolar Disorder Research Program, Department of Psychiatry, Emory University,
Objective: Stimulants have been used to treat ADHD or augment bipolar depression
treatment in patients with bipolar disorder (BD). However, the effects of
stimulant treatment in BD patients have been insufficiently studied. To date,
this is the largest study on amphetamine/ methylphenidate treatment and
associated mania/hypomania in BD patients. Method: Charts of patients evaluated
at the Emory Bipolar Disorder Specialty Clinic from 7/05 to 10/07 and diagnosed
with BD were randomly reviewed. Past diagnostic and treatment information were
obtained from patient reports and collateral information. Bipolar diagnosis and
past stimulant-associated mania were assessed by a board-certified psychiatrist
using Structured Clinical Diagnostic Interview. Methylphenidate, amphetamine, and
modafinil were considered stimulants. Multivariate regression models were used to
identify predictors of receiving stimulant treatment and of experiencing
stimulant-associated mania. Results: Of the 137 adult BD patients (72% BDI; 28%
BDII/ NOS), 25% had prior stimulant treatment for ADHD or bipolar depression.
Among those with prior stimulant treatment (21 with methylphenidate, 17 with
amphetamine, and 6 with modafinil), 43% were treated with a concurrent mood
stabilizer, and some with different types of stimulants sequentially. The rate of
stimulant-associated mania/hypomania was 40%. Having axis-I comorbidity, absence
of past substance addiction, and currently being unemployed were three factors
significantly associated with prior stimulant treatment. After adjusting for
important clinical variables, absence of axis-I comorbidity was associated with
stimulant-associated mania. Conclusions: BD patients commonly receive stimulant
treatment and often experience stimulant-associated mania/hypomania. More studies
are needed to examine the safety and efficacy of stimulant treatment in BD
PMID: 19015628 [PubMed – in process]
Am J Med Genet B Neuropsychiatr Genet. 2008 Dec 5;147B(8):1436-41.
A preliminary study of dopamine D4 receptor genotype and structural brain
alterations in adults with ADHD.
Monuteaux MC, Seidman LJ, Faraone SV, Makris N, Spencer T, Valera E, Brown A,
Bush G, Doyle AE, Hughes S, Helliesen M, Mick E, Biederman J.
Clinical and Research Program in Pediatric Psychopharmacology, Massachusetts
General Hospital, Boston, Massachusetts.
An emerging literature has demonstrated an association between the dopamine D4
receptor (DRD4) gene and volumetric brain abnormalities in children with ADHD.
However, these results have not been extended to adults and have not addressed
the impact of comorbidity. Our objective was to examine the DRD4 7R gene and
volumetric brain abnormalities in adults with ADHD while accounting for
comorbidity with bipolar disorder (BPD). Subjects were male and female adult
outpatient referrals stratified into two diagnostic groups: 24 with ADHD, 19 with
ADHD and BPD, as well as 20 male and female adult community controls without ADHD
or BPD. We measured volumes (cm(3)) of a priori selected brain regions (superior
frontal, middle frontal, anterior cingulate, and cerebellum cortices) by
structural magnetic resonance imaging. Among adults with ADHD, subjects with the
7-repeat allele of the DRD4 gene had a significantly smaller mean volume in the
superior frontal cortex and cerebellum cortex compared to subjects without this
allele. In contrast, no such effects were detected in the adults with ADHD + BPD
or controls. Our findings suggest that volumetric abnormalities in the
dorsolateral prefrontal cortex and cerebellum may represent an intermediate
neuroanatomical phenotype between DRD4 genotype and the clinical expression of
ADHD in adults, but only in ADHD subjects without comorbid BPD. These result
support the heterogeneity of ADHD and provides insights as to its underlying
pathophysiology. (c) 2008 Wiley-Liss, Inc.
PMID: 18951431 [PubMed – in process]
J Am Acad Child Adolesc Psychiatry. 2008 Aug 21. [Epub ahead of print]
CBCL Pediatric Bipolar Disorder Profile and ADHD: Comorbidity and Quantitative
Trait Loci Analysis.
McGough JJ, Loo SK, McCracken JT, Dang J, Clark S, Nelson SF, Smalley SL.
Drs. McGough and McCracken are with the Division of Child and Adolescent
Psychiatry at the UCLA Semel Institute for Neuroscience and Human Behavior and
David Geffen School of Medicine; Drs. Loo and Smalley and Mr. Dang are with the
Center for Neurobehavioral Genetics at the UCLA Semel Institute; and Dr. Nelson
and Ms. Clark are with the Center for Neurobehavioral Genetics at the UCLA Semel
Institute and Department of Human Genetics in the David Geffen School of
OBJECTIVE:: The pediatric bipolar disorder profilme of the Child Behavior
Checklist (CBCL-PBD), a parent-completed measure that avoids clinician
ideological bias, has proven useful in differentiating patients with
attention-deficit/hyperactivity disorder (ADHD). We used CBCL-PBD profiles to
distinguish patterns of comorbidity and to search for quantitative trait loci in
a genomewide scan in a sample of multiple affected ADHD sibling pairs. METHOD:: A
total of 540 ADHD subjects ages 5 to 18 years were assessed with the Schedule for
Affective Disorders and Schizophrenia for School-Age Children-Present and
Lifetime version and CBCL. Parents were assessed with the Schedule for Affective
Disorders and Schizophrenia-Lifetime version supplemented by the Schedule for
Affective Disorders and Schizophrenia for School-Age Children for disruptive
behavioral disorders. Patterns of psychiatric comorbidity were contrasted based
on the CBCL-PBD profile. A quantitative trait loci variance component analysis
was used to identify potential genomic regions that may harbor susceptibility
genes for the CBCL-PBD quantitative phenotype. RESULTS:: Bipolar spectrum
disorders represented less than 2% of the overall sample. The CBCL-PBD
classification was associated with increased generalized anxiety disorder (p
=.001), oppositional defiant disorder (p =.008), conduct disorder (p =.003), and
parental substance abuse (p =.005). A moderately significant linkage signal
(multipoint maximum lod score = 2.5) was found on chromosome 2q. CONCLUSIONS::
The CBCL-PBD profile distinguishes a subset of ADHD patients with significant
comorbidity. Linkage analysis of the CBCL-PBD phenotype suggests certain genomic
regions that merit further investigation for genes predisposing to severe
PMID: 18724256 [PubMed – as supplied by publisher]
Medicina (Kaunas). 2008;44(7):548-52.
Distinctions of bipolar disorder symptoms in adolescence.
Gudiene D, Leskauskas D, Markevici?te A, Klimavicius D, Adomaitiene V.
Department of Psychiatry, Unit of Children’s and Adolescents’ Psychiatry,Kaunas
University of Medicine, Kaunas, Lithuania. firstname.lastname@example.org
Bipolar disorder in adolescents is a serious mental illness with problematic
diagnosis that adversely affects social, academic, emotional, and family
functioning. The objective of this study was to analyze features of premorbid and
clinical symptoms, comorbidity, and course of bipolar disorder in adolescence.
Data for analysis were collected from all case histories (N=6) of 14-18-year-old
patients, hospitalized with diagnosis of bipolar disorder in the Unit of
Children’s and Adolescents’ Psychiatry, Department of Psychiatry, Hospital of
Kaunas University of Medicine, during the period from 2000 to 2005. Analysis of
bipolar disorder course showed that five patients previously had been diagnosed
with an episode of depression. The most frequent symptoms typical to bipolar
disorder were disobedience and impulsive behavior, rapid changes of mood. The
most common premorbid features were frequent changes of mood, being active in
communication, hyperactive behavior. Adolescence-onset bipolar disorder was
frequently comorbid with emotionally instable personality disorder, borderline
type. Findings of the study confirm the notion that oppositional or impulsive
behavior, rapid changes of mood without any reason, dysphoric mood and euphoric
mood episodes with increased energy were cardinal symptoms of bipolar disorder
with mania in adolescents. Most frequent premorbid features of these patients
were quite similar to attention-deficit/hyperactivity disorder making
differential diagnosis problematic.
PMID: 18695352 [PubMed – indexed for MEDLINE]
J Affect Disord. 2008 Jul 14. [Epub ahead of print]
Long-term outcomes of youth who manifested the CBCL-Pediatric Bipolar Disorder
phenotype during childhood and/or adolescence.
Meyer SE, Carlson GA, Youngstrom E, Ronsaville DS, Martinez PE, Gold PW, Hakak R,
Division of Child and Adolescent Psychiatry, Cedars-Sinai Medical Center, Los
Angeles, CA, United States.
OBJECTIVE: Recent studies have identified a Child Behavior Checklist (CBCL)
profile that characterizes children with severe aggression, inattention, and mood
instability. This profile has been coined the CBCL-Pediatric Bipolar Disorder
(PBD) phenotype, because it is commonly seen among children with bipolar
disorder. However, mounting evidence suggests that the CBCL-PBD may be a better
tool for identifying children with severe functional impairment and broad-ranging
psychiatric comorbidities rather than bipolar disorder itself. No studies have
followed individuals with the CBCL-PBD profile through adulthood, so its
long-term implications remain unclear. The present authors examined diagnostic
and functional trajectories of individuals with the CBCL-PBD profile from early
childhood through young adulthood using data from a longitudinal high-risk study.
METHOD: Participants (n=101) are part of a 23-year study of youth at risk for
major mood disorder who have completed diagnostic and functional assessments at
regular intervals. RESULTS: Across development, participants with the CBCL-PBD
phenotype exhibited marked psychosocial impairment, increased rates of suicidal
thoughts and behaviors and heightened risk for comorbid anxiety, bipolar
disorder, cluster B personality disorders and ADHD in young adulthood, compared
to participants without this presentation. However, diagnostic accuracy for any
one particular disorder was found to be low. CONCLUSIONS: Children with the
CBCL-PBD profile are at risk for ongoing, severe, psychiatric symptomatology
including behavior and emotional comorbidities in general, and bipolar disorder,
anxiety, ADHD, cluster B personality disorders in particular. However, the value
of this profile may be in predicting ongoing comorbidity and impairment, rather
than any one specific DSM-IV diagnosis.
PMID: 18632161 [PubMed – as supplied by publisher]
Child Adolesc Psychiatry Ment Health. 2008 Jul 3;2(1):15.
ADHD characteristics: I. Concurrent co-morbidity patterns in children &
Elia J, Ambrosini P, Berrettini W.
Department of Child and Adolescent Psychiatry, The Children’s Hospital of
Philadelphia, Philadelphia, PA, USA. email@example.com.
ABSTRACT: OBJECTIVE: 342 Caucasian subjects with attention deficit/hyperactivity
disorder (ADHD) were recruited from pediatric and behavioral health clinics for a
genetic study. Concurrent comorbidity was assessed to characterize the clinical
profile of this cohort. METHODS: Subjects 6 to 18 years were diagnosed with the
Schedule for Affective Disorders & Schizophrenia for School aged Children
(K-SADS-P IVR). RESULTS: The most prevalent diagnoses co-occurring with ADHD were
Oppositional Defiant Disorder (ODD) (40.6%), Minor Depression/Dysthymia (MDDD)
(21.6%), and Generalized Anxiety Disorder (GAD) (15.2%). In Inattentive ADHD (n =
106), 20.8% had MDDD, 20.8% ODD, and 18.6% GAD; in Hyperactive ADHD (n = 31)
41.9% had ODD, 22.2% GAD, and 19.4% MDDD. In Combined ADHD, (n = 203), 50.7% had
ODD, 22.7% MDDD and 12.4% GAD. MDDD and GAD were equally prevalent in the ADHD
subtypes but, ODD was significantly more common among Combined and Hyperactive
ADHD compared to Inattentive ADHD. The data suggested a subsample of Irritable
prepubertal children exhibiting a diagnostic triad of ODD, Combined ADHD, and
MDDD may account for the over diagnosing of Bipolar Disorder. CONCLUSION: Almost
2/3rd of ADHD children have impairing comorbid diagnoses; Hyperactive ADHD
represents less than 10% of an ADHD sample; ODD is primarily associated with
Hyperactive and Combined ADHD; and, MDDD may be a significant morbidity for ADHD
youths from clinical samples.
PMID: 18598351 [PubMed – in process]
J Child Adolesc Psychopharmacol. 2008 Jun;18(3):271-9.
Comorbidity of conduct disorder and bipolar disorder in clinically referred
children and adolescents.
Masi G, Milone A, Manfredi A, Pari C, Paziente A, Millepiedi S.
IRCCS Stella Maris, Scientific Institute of Child Neurology and Psychiatry,
Calambrone, Pisa, Italy. firstname.lastname@example.org
OBJECTIVE: The co-occurrence of conduct disorder (CD) and bipolar disorder (BD)
has been frequently reported in referred children and adolescents. We address the
implications of this comorbidity in a naturalistic sample of youths with BD, CD,
and CD+BD. METHODS: The sample consisted of 307 patients (216 males and 91
females, age range 8-18 years, mean age 13.5 +/- 2.6 years) referred during a
5-year period and followed-up for at least 6 months, 106 with CD without BD, 109
with BD without CD, and 92 with CD+BD, diagnosed with a structured clinical
interview (K-SADS-PL). RESULTS: Patients with CD alone were more predominantly
males and with the lowest socio-economic status. Patients with CD without BD were
the least severe at the baseline, while patients with BD alone presented the
greatest improvement during the follow-up, and those with CD+BD had the poorest
response. Patients with CD+BD presented higher rates of global aggression at the
baseline, namely impulsive aggression, compared with CD alone, and the highest
risk of substance abuse. Patients with BD alone presented higher rates of
comorbid panic disorder and obsessive compulsive disorder, while patients with
CD, with or without BD, had higher rates of ADHD. CONCLUSIONS: Bipolar-conduct
disorder comorbidity may have meaningful implications in children and
adolescents, in terms of presentation, course, and treatments.
PMID: 18582182 [PubMed – in process]
Eur Arch Psychiatry Clin Neurosci. 2008 Oct;258(7):385-93. Epub 2008 Apr 24.
Comorbidity of adult attention-deficit hyperactivity disorder and bipolar
disorder: prevalence and clinical correlates.
Tamam L, Karakus G, Ozpoyraz N.
Department of Psychiatry, Cukurova University Faculty of Medicine, Adana, Turkey,
The aim of this study was to determine the frequency of adult attention deficit
hyperactivity disorder (ADHD) comorbidity with lifetime bipolar disorder, and the
influence of this comorbidity on various demographic and clinical variables in
patients. Patients (n = 159) with a previous diagnosis of bipolar disorder (79
female, 80 male) were included in this study. All patients were interviewed for
the presence of current adult and childhood ADHD diagnosis and other axis I
psychiatric disorder comorbidities using the structured clinical interview for
DSM-IV (SCID) and the Schedule for Affective Disorders and Schizophrenia for
School Age Children-Present and Lifetime Version (K-SADS-PL). The subjects also
completed a Wender Utah rating scale (WURS-25) and a Current Symptoms Scale for
ADHD symptoms. In particular, patients’ clinical characteristics, the age of
onset of bipolar disorder, and the number of episodes were noted. Twenty-six of
the 159 bipolar patients (16.3%) were diagnosed with adult ADHD, while another
subgroup of patients (n = 17, 10.7%) received a diagnosis of childhood ADHD but
did not fulfill criteria for adult ADHD. Both of these two subgroups (patients
with adult ADHD, and patients with only childhood ADHD) had an earlier age of
onset of the disease and a higher number of previous total affective or
depressive episodes than those without any lifetime ADHD comorbidity. However
only bipolar patients with adult ADHD comorbidity had higher lifetime comorbidity
rates for axis I psychiatric disorders, such as panic disorder and alcohol
abuse/dependence, compared to patients without lifetime ADHD. Bipolar patients
with comorbid adult ADHD did not differ from bipolar patients with comorbid
childhood ADHD in terms of any demographic or clinical variables except for adult
ADHD scale scores. In conclusion, ADHD is a common comorbidity in bipolar
patients, and it adversely affects the course of the disease and disrupts the
social adjustment of the patients. Regular monitoring of ADHD will help to
prevent problems and complications that could arise in the course of the disease,
particularly in patients with early onset bipolar disorder.
PMID: 18437277 [PubMed – in process]
Int Rev Psychiatry. 2008 Apr;20(2):171-6.
Mood lability and bipolar disorder in children and adolescents.
Miller L, Barnett S.
Division of Child and Adolescent Psychiatry, Department of Psychiatry and
Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, USA.
Pediatric bipolar disorder, once considered rare, has reportedly increased in
incidence over the past 10 years. There is significant debate about the
phenomenology, diagnosis and treatment of this illness. The diagnostic assessment
of children with severe mood and behavioural disturbance is of considerable
public health importance as the ultimate diagnosis can have significant treatment
implications and can impact the level of stigma experienced by children and their
families. The purposes of this paper are to: 1) review current issues in the
phenomenology and diagnostic assessment of bipolar disorder in children and
adolescents; 2) review recent research suggesting that youths with a chronic
course of illness should be considered a separate group from those with an
episodic course; and 3) offer suggestions for future studies to address the
various phenomenological controversies.
PMID: 18386208 [PubMed – indexed for MEDLINE]
Curr Med Res Opin. 2008 May;24(5):1345-57. Epub 2008 Apr 1.
A qualitative review of issues arising in the use of psycho-stimulant medications
in patients with ADHD and co-morbid substance use disorders.
Department of Psychiatry, Duke ADHD Program, Duke University, Durham, NC 27705,
OBJECTIVE: This review addresses the relationship between
attention-deficit/hyperactivity disorder (ADHD) and substance use disorders
(SUDs), with an emphasis on factors that determine the potential for
psychostimulant abuse. Strategies for identification and treatment of patients
with ADHD who are at risk for, or have, co-morbid SUD are also addressed.
RESEARCH DESIGN AND METHODS: The article was based on a qualitative review of
current literature addressing co-morbid ADHD and SUD. DISCUSSION: Adolescent and
adult patients with ADHD are at increased risk for SUD, as well as a number of
other psychiatric disorders. Psychostimulant agents like methylphenidate (MPH)
and mixed amphetamine salts (MAS) are effective first-line pharmacotherapies for
ADHD; however, they are Schedule II controlled substances with a potential for
abuse. Evidence suggests that treatment of ADHD during childhood with stimulant
agents may reduce the risk of developing SUD later on. Factors associated with
the highest risk of SUD in patients with ADHD include co-morbid antisocial
personality disorder, bipolar disorder, an eating disorder, severe ADHD and/or
antisocial behavior symptoms, and dropping out of school. Treatment initiation
during adolescence or young adulthood also has been linked to increased risk of
polydrug use and non-medical stimulant use, a pattern of behavior consistent with
a risk of SUD development. Treatment plans for patients with ADHD and co-morbid
SUD should include behavioral interventions, careful monitoring, and when
appropriate, pharmacotherapy. When oral formulations of psychostimulants are used
at recommended doses and frequencies, they are unlikely to yield effects
consistent with abuse potential in patients with ADHD. Long-acting stimulant
formulations and non-stimulants, like atomoxetine or bupropion, have a lower
potential for abuse, and provide several safe and effective treatment options for
the development of a comprehensive management plan for patients with co-morbid
ADHD and SUD. CONCLUSIONS: The present review is neither exhaustive nor
systematic. Moreover, the reviewed studies vary widely with regards to
methodology and patient populations. In light of these limitations, several
conclusions are still warranted. Patients with ADHD are at increased risk for
SUD. Under certain conditions, psychostimulants may be a pharmacologic option in
the treatment of patients with co-morbid ADHD and SUD. However, clinicians should
be mindful of the risks and benefits of this treatment approach in a high-risk
population and should also bear in mind the labeling guidelines when working with
PMID: 18384709 [PubMed – indexed for MEDLINE]
Pediatr Nurs. 2008 Jan-Feb;34(1):84-8.
Bipolar disorders: symptoms and treatment in children and adolescents.
Apps J, Winkler J, Jandrisevits MD.
Child and Adolescent Psychiatry, Medical College of Wisconsin, Milwaukee, WI,
Bipolar disorders are being diagnosed with increasing frequency in children and
adolescents, resulting in a need for nurses in a wide variety of settings to be
aware of symptom presentation and treatment options. Symptoms can be
conceptualized in a developmental context based on the Diagnostic and Statistical
Manual (DSM-IV TR) criteria. Symptoms of mania can be distinguished from other
disorders, including Attention Deficit Hyperactivity Disorder, even when these
disorders co-occur. Treatment options can include single or combination
psychopharmacologic therapy, using a variety of mood stabilizers, atypical
antipsychotic agents and subsequent treatment of residual ADHD symptoms.
Additionally, therapeutic interventions for the child and family are important.
While additional research is needed, appropriate treatment of pediatric bipolar
disorders can lead to significant improvements in functioning and development.
PMID: 18361094 [PubMed – indexed for MEDLINE]
J Clin Psychol. 2008 Apr;64(4):382-401.
Comparing the psychometric properties of multiple teacher report instruments as
predictors of bipolar disorder in children and adolescents.
Youngstrom EA, Joseph MF, Greene J.
Department of Psychology, University of North Carolina, Chapel Hill, NC
27599-3270, USA. email@example.com
The psychometric properties of four teacher report measures and their utility for
accurate diagnosis of pediatric bipolar spectrum disorders (BPSDs) were examined.
Participants were 191 youth (65% male; 62% African-American; 23% diagnosed with a
BPSD), age 5-18 (M=10.16, SD=3.27) years, 70% recruited from a community mental
health center and 30% recruited from a mood disorders clinic. Teachers “who knew
the child best” were asked to complete the Achenbach Teacher Report Form (TRF) as
well as teacher versions of the General Behavior Inventory (T-GBI), the Child
Mania Rating Scale (CMRS-T), and the Young Mania Rating Scale (T-YMRS). Teacher
response rates and missing data varied significantly depending on the age of the
child. Exploratory factor analysis identified stable and interpretable factors;
however, receiver operating characteristic (ROC) and logistic regression analyses
showed that teacher report measures were not able to discriminate BPSD cases from
non-BPSD cases, or from attention deficit hyperactivity disorder (ADHD) cases.
Teacher report appears to be insufficiently specific or sensitive to BPSD for
clinical diagnostic use, although teacher scales might have research utility.
PMID: 18300293 [PubMed – indexed for MEDLINE]
J Clin Psychiatry. 2007 Nov;68(11):1776-84.
A systematic review of rates and diagnostic validity of comorbid adult
attention-deficit/hyperactivity disorder and bipolar disorder.
Wingo AP, Ghaemi SN.
Bipolar Disorder Research Program, Department of Psychiatry and Behavioral
Sciences, Emory University, Atlanta, Ga. 30322, USA. firstname.lastname@example.org
OBJECTIVE: Adult attention-deficit/hyperactivity disorder (ADHD) is increasingly
recognized and reported to frequently coexist with bipolar disorder. Concurrent
diagnosis of adult ADHD and bipolar disorder remains controversial. In this
study, we conducted a systematic review to examine the rates and diagnostic
validity of the concept of comorbid adult ADHD and bipolar disorder. DATA
SOURCES: MEDLINE, Embase, PsycInfo, and Cochrane databases were searched for
articles published before March 30, 2007, using the keywords manic, bipolar,
attention deficit hyperactivity, and adult. The computer search was supplemented
with bibliographic cross-referencing. STUDY SELECTION: Exclusion criteria were
studies with only pediatric subjects, childhood ADHD only but not adult ADHD, and
either bipolar disorder or ADHD only, but not both; review articles, case
reports; letters to the editor; and book chapters. Of the 262 citations found, 12
studies met our inclusion criteria. DATA EXTRACTION: Specific diagnostic
validating criteria examined were phenomenology, course of illness, heredity,
biological markers, and treatment response. There were 6 studies on comorbid
rates, 4 on phenomenology, 3 on course of illness, 2 on heredity, none on
biological markers, and 1 on treatment response. DATA SYNTHESIS: The proposed
comorbid syndrome is fairly common (present in up to 47% of adult ADHD and 21% of
bipolar disorder populations), with a more severe course of illness compared with
that of bipolar disorder alone, and high rates of comorbidity with other
psychiatric disorders. Its treatment appears to require initial mood
stabilization. CONCLUSIONS: Comorbid adult ADHD and bipolar disorder has been
insufficiently studied, with more emphasis on comorbidity rates and few data on
course, neurobiology, heredity, and treatment. The diagnostic validity of adult
ADHD/ bipolar disorder as a true comorbidity is not well-established on the basis
of this equivocal and insufficient literature. More studies are greatly needed to
further clarify its diagnostic validity and treatment approach.
PMID: 18052572 [PubMed – indexed for MEDLINE]
CNS Spectr. 2007 Aug;12(8 Suppl 12):1-14; quiz 15-6.
The complexity of ADHD: diagnosis and treatment of the adult patient with
Newcorn JH, Weiss M, Stein MA.
Division of Child and Adolescent Psychiatry, Department of Psychiatry, The Mount
Sinai School of Medicine, New York, NY, USA.
Attention-deficit/hyperactivity disorder (ADHD) is an impairing but usually
treatable condition. Popular culture propagates the myth that ADHD recedes with
age; this is not the case. Although it is common, <20% of adults with ADHD are
diagnosed or treated. Adults with ADHD show significant comorbidities with
depressive disorders, anxiety disorders, substance use, oppositional defiant
disorder, personality disorders, sleep problems, and learning disabilities.
However, symptoms that result from ADHD, such as mood symptoms or lability, are
often mistaken for comorbid disorders. Comorbidity with ADHD impacts treatment
compliance, treatment response, and patient insight. Insufficient data on the
interaction between ADHD and comorbidities impedes proper diagnosis and
treatment. Better clinical tools for assessing these conditions are needed. Food
and Drug Administration-approved pharmacologic treatments for adult ADHD include
stimulants, dexmethylphenidate, and the nonstimulant atomoxetine. Effect sizes of
approved medicines at approved doses are half those seen in children. Adults may
also need longer duration of medication effects than children. Short-acting
stimulants are likely to result in poorer adherence and have a higher risk for
diversion or abuse. Risk of abuse is a major concern; stimulant treatments are
controlled substances, and children with ADHD show increased risk of substance
abuse. Psychosocial interventions may be beneficial in treating both ADHD and
comorbidities.In this expert roundtable supplement, Margaret Weiss, MD, PhD,
presents a comprehensive overview of complications surrounding differential
diagnosis in adults with ADHD. Next, Mark A. Stein, PhD, reviews evaluation,
comorbidity, and development of a treatment plan in this population. Finally,
Jeffrey H. Newcorn, MD, provides a discussion on the pharmacologic options
available for adults with ADHD, considering dosages specific to adults and common
PMID: 17667893 [PubMed – indexed for MEDLINE]
J Clin Psychiatry. 2007 Oct;68(10):e25.
Bipolar mixed episodes: characteristics and comorbidities.
Goldberg JF, McElroy SL.
Mt. Sinai School of Medicine, New York, NY, USA.
Mixed episodes are associated with greater total lifetime costs, increased
suicide risk, and increased substance misuse than pure manic episodes and may
resemble depressive episodes due to similar quality of life scores, cognitive
styles, and likelihood of cycling to depression. Patients with mixed states have
an increased potential for abnormally low cholesterol, hypothyroidism, and other
medical comorbidities that can slow recovery. In addition, patients with mixed
states can have comorbid anxiety disorders and ADHD.
PMID: 17960958 [PubMed – indexed for MEDLINE]
Psychol Med. 2008 Jul;38(7):1045-56. Epub 2007 Oct 15.
Towards further understanding of the co-morbidity between attention deficit
hyperactivity disorder and bipolar disorder: a MRI study of brain volumes.
Biederman J, Makris N, Valera EM, Monuteaux MC, Goldstein JM, Buka S, Boriel DL,
Bandyopadhyay S, Kennedy DN, Caviness VS, Bush G, Aleardi M, Hammerness P,
Faraone SV, Seidman LJ.
Clinical and Research Program in Pediatric Psychopharmacology, Psychiatry
Department, Massachusetts General Hospital, Boston, MA 02114, USA.
BACKGROUND: Although attention deficit hyperactivity disorder (ADHD) and bipolar
disorder (BPD) co-occur frequently and represent a particularly morbid clinical
form of both disorders, neuroimaging research addressing this co-morbidity is
scarce. Our aim was to evaluate the morphometric magnetic resonance imaging (MRI)
underpinnings of the co-morbidity of ADHD with BPD, testing the hypothesis that
subjects with this co-morbidity would have neuroanatomical correlates of both
disorders. METHOD: Morphometric MRI findings were compared between 31 adults with
ADHD and BPD and with those of 18 with BPD, 26 with ADHD, and 23 healthy
controls. The volumes (cm(3)) of our regions of interest (ROIs) were estimated as
a function of ADHD status, BPD status, age, sex, and omnibus brain volume using
linear regression models. RESULTS: When BPD was associated with a significantly
smaller orbital prefrontal cortex and larger right thalamus, this pattern was
found in co-morbid subjects with ADHD plus BPD. Likewise, when ADHD was
associated with significantly less neocortical gray matter, less overall frontal
lobe and superior prefrontal cortex volumes, a smaller right anterior cingulate
cortex and less cerebellar gray matter, so did co-morbid ADHD plus BPD subjects.
CONCLUSIONS: Our results support the hypothesis that ADHD and BPD independently
contribute to volumetric alterations of selective and distinct brain structures.
In the co-morbid state of ADHD plus BPD, the profile of brain volumetric
abnormalities consists of structures that are altered in both disorders
individually. Attention to co-morbidity is necessary to help clarify the
heterogeneous neuroanatomy of both BPD and ADHD.
PMID: 17935640 [PubMed – indexed for MEDLINE]
CNS Spectr. 2007 Oct;12(10):758-62.
Aripiprazole in juvenile bipolar disorder comorbid with
attention-deficit/hyperactivity disorder: an open clinical trial.
Tramontina S, Zeni CP, Pheula GF, de Souza CK, Rohde LA.
Attention-Deficit/Hyoeractivity Disorder, Division of Child and Adolescent
Psychiatry, Hospital de ClÃnicas de Porto Alegre at the Federal University of Rio
Grande do Sul, Rio Grande do Sul, Brazil.
INTRODUCTION: Juvenile bipolar disorder (JBD) is a highly impairing chronic
mental health condition that affects children and adolescents’ overall
functioning. Comorbidity with attention-deficit/hyperactivity disorder (ADHD) is
extremely prevalent and may determine worse response to treatment. Few
investigations have addressed the use of recent atypical antipsychotics in JBD,
although several guidelines suggest their use. METHODS: We conducted a 6-week
open trial with aripiprazole in 10 children and adolescents with JBD comorbid
with ADHD to assess impact on mania and ADHD symptoms, respectively, by means of
the Young Mania Rating Scale and the Swanson, Nolan and Pelham Scale, as well as
on global functioning (Clinical Global Impressions-Severity), and adverse events.
RESULTS: Significant improvement in global functioning scores (F=3.17, P=.01,
effect size=0.55), manic symptoms (F=5.63, P<.01; ES=0.93), and ADHD symptoms
(t=3.42, P<.01;ES=1.05) were detected. Although an overall positive tolerability
was reported, significant weight gain (F=3.07, P=.05) was observed. CONCLUSION:
Aripiprazole was effective in improving mania and ADHD symptoms, but neither JBD
nor ADHD symptom remission was observed in most of the cases. Randomized
placebo-controlled trials for JBD and ADHD are needed.
Curr Psychiatry Rep. 2007 Oct;9(5):415-9.
Concurrent ADHD and bipolar disorder.
Department of Psychiatry and Behavioral Sciences, Kansas University Medical
Center-Wichita, 1010 North Kansas, Wichita, KS 67214-3199, USA.
Attention-deficit/hyperactivity disorder (ADHD) frequently is present
concurrently with bipolar disorder (BPD) in youth. This concurrence appears to be
more common in younger children. The degree to which ADHD is present in adults
with BPD has not been well studied. The psychiatric and behavioral symptoms
associated with ADHD and BPD have significant overlap. The core symptoms of BPD
are relatively independent and respond to different pharmacologic and behavioral
strategies. Although much symptomatic overlap exists between ADHD and BPD, these
conditions can be reliably differentiated from each other and require independent
treatments that frequently need to be sequenced.
PMID: 17915082 [PubMed – indexed for MEDLINE]
Rev Med Suisse. 2007 May 30;3(113):1406-10, 1412.[Bipolar paediatric disorder early diagnosis] [Article in French]
Macias M, Bryois C.
Service mÃ©dico-pÃ©dagogique vaudois 15, avenue de la Gare, 1110 Morges.
The Bipolar Disorder in infants and youngsters is not very known and
under-diagnosed in the concerned population. We hereby describe its clinical
features, its comorbidity along with other frequent psychopathologies, such as
ADHD, which enable us to describe the symptoms and the indicators of risk.
According to how these indicators appear, we can establish various degrees of
clinical risk. Irritability, impulsiveness, hyperactivity, intolerance to
frustration and sleep disorders are the most frequent prodroms. If they present a
clinic of suicidality, toxic abuse (cannabis, alcohol), or even psychotic
symptoms, in the context of significant family history, the child psychiatrist
should not doubt to diagnose Bipolar Disorder and start the corresponding
PMID: 17645056 [PubMed – indexed for MEDLINE]
Psychiatry Res. 2007 Sep 30;153(1):47-54. Epub 2007 Jun 28.
Clinical and research implications of panic-bipolar comorbidity in children and
Masi G, Perugi G, Millepiedi S, Toni C, Mucci M, Bertini N, Pfanner C, Berloffa
S, Pari C, Akiskal K, Akiskal HS.
IRCCS Stella Maris, Scientific Institute Child Neurology and Psychiatry,
Calambrone, Pisa, Italy. email@example.com
A substantial portion of patients with juvenile bipolar disorder (BD) have a
comorbid panic disorder (PD). The aim of our study was to analyze the
cross-sectional and longitudinal implications of such comorbidity in children and
adolescents with BD. The sample comprised 224 referred children and adolescents
with BD, 140 males (62.5%) and 84 females (37.5%), mean age 13.8+/-2.8 years,
diagnosed with a clinical interview (K-SADS-PL), and followed up naturalistically
for 6 months. Fifty-one BD patients (22.8%) had a lifetime diagnosis of comorbid
PD. Subjects with BD+PD and those without BD (BD-noPD) did not differ according
to index age, age at onset of BD and bipolar phenotype (episodic vs. continuous
course, irritable vs. elated mood). BD+PD was more frequent in females, was less
severe at baseline according to the Clinical Global Impression severity score,
and was more frequently associated with BD type 2. Moreover, BD+PD presented
higher rates of comorbid anxiety disorders (namely separation anxiety disorder)
and lower rates of externalizing disorders, namely attention deficit disorder
(ADHD) than BD-noPD. However, this different pattern of externalizing comorbidity
did not affect severity and improvement. Our findings suggest that PD is
frequently comorbid in juvenile BD and can influence severity, pattern of
comorbidity and course of BD. The data are compatible with the hypothesis that
Panic-BD and ADHD-BD might represent distinct developmental pathways of bipolar
disorder. Further research on this question may prove rewarding.
PMID: 17602754 [PubMed – indexed for MEDLINE]
Can J Psychiatry. 2007 May;52(5):323-8.
Comorbidity with ADHD decreases response to pharmacotherapy in children and
adolescents with acute mania: evidence from a metaanalysis.
Consoli A, Bouzamondo A, GuilÃ© JM, Lechat P, Cohen D.
Department of Child and Adolescent Psychiatry, AP-HP, HÃ´pital PitiÃ©-SalpÃ©triÃ¨re,
UniversitÃ© Pierre et Marie Curie, Paris, France.
OBJECTIVE: To assess whether comorbid attention-deficit hyperactivity disorder
(ADHD) influences response to treatment in young patients with acute mania.
METHODS: We conducted a metaanalysis of 5 open trials of 100, 35, 41, 60, and 37
children and adolescents. The pooled group included 273 children and adolescents
with bipolar disorder (BD), divided into 2 subgroups: those with (n = 132), and
those without (n = 141), ADHD comorbidity. RESULTS: There was a moderate and
significant reduction in relative risk (RR) favouring treatment response in
children and adolescents with BD but without ADHD comorbidity (RR 0.822; 95% CI,
0.69 to 0.97; P = 0.021). The negative effect of ADHD comorbidity on treatment
response was more significant in studies including adolescents only or subjects
with BD I only. CONCLUSION: These findings suggest that children and adolescents
with BD and ADHD tend to be less responsive to drugs used in treatment of acute
PMID: 17542383 [PubMed – indexed for MEDLINE]
J Consult Clin Psychol. 2007 Apr;75(2):210-20.
Can bipolar disorder-specific neuropsychological impairments in children be
Henin A, Mick E, Biederman J, Fried R, Wozniak J, Faraone SV, Harrington K, Davis
S, Doyle AE.
Pediatric Psychopharmacology Unit, Massachusetts General Hospital, Cambridge, MA
02138, USA. firstname.lastname@example.org
This study examined neuropsychological deficits among children with bipolar
disorder while attending to its comorbidity with attention-deficit/hyperactivity
disorder (ADHD). Seventy-three unmedicated children (ages 6-17 years) with
Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American
Psychiatric Association, 1994) bipolar disorder plus ADHD (BPD + ADHD) were
compared with 102 unmedicated children with ADHD without bipolar disorder, and
120 children without bipolar disorder or ADHD. Ninety-four percent of
participants were Caucasian, 58% were male, and 42% were female. On average
participants were of middle to upper socioeconomic status. Participants were
assessed with a comprehensive neuropsychological battery and measures of academic
achievement, school failure, and special education placement. Participants with
BPD + ADHD and with ADHD were impaired in interference control, verbal learning,
and arithmetic achievement and had higher rates of special school services.
Across all of the measures of neuropsychological functioning, the only difference
observed between youths with BPD + ADHD and youths with ADHD was that youths with
BPD + ADHD performed more poorly on one measure of processing speed. Thus,
comorbidity with ADHD may account for many of the neuropsychological deficits
observed in children with bipolar disorder. Copyright 2007 APA, all rights
PMID: 17469879 [PubMed – indexed for MEDLINE]
Bipolar Disord. 2007 May;9(3):243-51.
Differentiating bipolar disorder in Turkish prepubertal children with
attention-deficit hyperactivity disorder.
Diler RS, Uguz S, Seydaoglu G, Erol N, Avci A.
Department of Psychiatry, Western Psychiatric Institute and Clinic, University of
Pittsburgh, Pittsburgh, PA 15213, USA. email@example.com
BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) and bipolar disorder
(BPD) in children are frequently comorbid conditions. Because the coexistence of
ADHD and mania seriously complicates the course of the condition and the
treatment of children, diagnosing or missing this comorbidity has important
clinical implications. There are very few systematic studies on the subject in
the literature and BPD in children is not recognized or studied in most countries
other than the USA. We aimed to differentiate Turkish prepubertal children with
ADHD from those with comorbid ADHD and BPD and compare their clinical
characteristics. METHODS: A total of 147 treatment- and drug-naÃ¯ve children, aged
7 to 13 years, who had been consecutively referred to the ADHD clinic, were
evaluated using the Schedule for Affective Disorders and Schizophrenia for
School-age Children-Present and Lifetime version (K-SADS-PL). Parents completed
the Child Behavior Checklist (CBCL) 4-18 and the Parent-Young Mania Rating Scale
(P-YMRS) prior to the clinical interview. RESULTS: Twelve children (8.2%) had
comorbid bipolar disorder (ADHD + BPD). The ADHD + BPD group had significantly
higher rates of depressive disorders, oppositional defiant disorder, panic
disorder and a family history of bipolar disorder compared with the ADHD group.
The ADHD + BPD group had significantly more problems on the CBCL scale
(anxiety/depression, social problems, thought problems, aggression,
externalization, and total score) and on the P-YMRS (all items except for
insight) compared with the ADHD group. CONCLUSIONS: We conclude that ADHD + BPD
in Turkish children represents a clinical picture different to that of ADHD
alone, in which the clinical characteristics resemble those of children reported
in the literature. Further long-term follow-up studies are needed in larger
clinical and community samples.
PMID: 17430299 [PubMed – indexed for MEDLINE]
Am J Psychiatry. 2007 Apr;164(4):582-90.
Am J Psychiatry. 2007 Apr;164(4):537-9.
Twelve-month outcome of adolescents with bipolar disorder following first
hospitalization for a manic or mixed episode.
DelBello MP, Hanseman D, Adler CM, Fleck DE, Strakowski SM.
Division of Bipolar Disorders Research, University of Cincinnati College of
Medicine, Cincinnati, OH 45267-0559, USA. firstname.lastname@example.org
OBJECTIVE: Although adolescent-onset bipolar disorder is associated with
significant morbidity, there have been few prospective outcome studies of this
population. The aim of this study was to examine the 12-month outcome of bipolar
adolescents following an initial hospitalization for a manic or mixed episode.
METHOD: Bipolar adolescents (N=71) were recruited during their first
hospitalization for a manic or mixed episode and were evaluated using diagnostic,
symptomatic, and functional assessments. Patients were also evaluated at 1, 4, 8,
and 12 months after hospitalization to assess syndromic, symptomatic, and
functional outcomes. Predictors of each type of outcome were identified. RESULTS:
Kaplan-Meier estimates of the cumulative probabilities of syndromal, symptomatic,
and functional recovery and syndromic recurrence during the first 12 months
following initial hospitalization were 0.86, 0.43, 0.41, and 0.54, respectively.
Only 35% of bipolar adolescents reported full medication adherence. Individual
predictors of poor syndromic recovery included co-occurring attention deficit
hyperactivity disorder (ADHD), anxiety disorders, and disruptive behavior
disorders as well as nonadherence to psychotropic medication and lower
socioeconomic levels. Co-occurring alcohol use disorders, treatment with
antidepressants, and the absence of psychotherapeutic intervention predicted
syndromic recurrence. Boys were more than twice as likely as girls to experience
symptomatic recovery. CONCLUSIONS: Most bipolar adolescents experienced syndromic
recovery following their first hospitalization. However, rates of symptomatic and
functional recoveries were much lower. Future studies examining effective
pharmacological and nonpharmacological treatment strategies for bipolar youth
with co-occurring disorders and investigating factors that contribute to the
development of substance use disorders and treatment adherence in bipolar youth
are necessary to improve outcome.
PMID: 17403971 [PubMed – indexed for MEDLINE]
Expert Opin Pharmacother. 2007 Apr;8(5):555-62.
Treating common psychiatric disorders associated with
Kunwar A, Dewan M, Faraone SV.
Department of Psychiatry, State University of New York–Upstate Medical
University, Syracuse, NY 13210 USA.
Attention-deficit/hyperactivity disorder (ADHD) often occurs along with other
psychiatric disorders, with estimated comorbidity rates of 50–90%. Comorbidity
greatly influences presentation, diagnosis and prognosis, complicates treatment
and significantly increases the morbidity and disease burden of ADHD. Commonly
co-occurring psychiatric disorders are disruptive behavior disorder, anxiety,
depression, bipolar disorder and substance use disorders. This article provides a
brief review of effective strategies for treating the most common psychiatric
disorders associated with ADHD. This paper also discusses knowledge gaps in the
understanding of treatment of comorbid disorders associated with ADHD, and
directions for future research.
PMID: 17376012 [PubMed – indexed for MEDLINE]
J Child Adolesc Psychopharmacol. 2006 Dec;16(6):679-85.
Developmental differences according to age at onset in juvenile bipolar disorder.
Masi G, Perugi G, Millepiedi S, Mucci M, Toni C, Bertini N, Pfanner C, Berloffa
S, Pari C.
IRCCS Stella Maris, Scientific Institute of Child Neurology and Psychiatry,
Calambrone, Pisa, Italy. email@example.com
BACKGROUND: This study on a large sample of unselected, consecutive children and
adolescents referred to a third-level hospital who received a diagnosis of
bipolar disorder (BD) was aimed at exploring whether childhood-onset BD, as
compared with adolescent-onset BD, presents specific clinical features in terms
of severity, functional impairment, course, prevalent mood, pattern of
co-morbidity, and treatment outcome. METHODS: A total of 136 patients, 81 males
(59.6%) and 55 females (40.4%), mean age 13.5 +/- 2.9 years, meeting the
Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)
diagnosis of BD according to a structured clinical interview Schedule for
Affective Disorders and Schizophrenia for School-Age Children-Present and
Lifetime Version (KSADS-PL), were included in the study. RESULTS: Eighty patients
(58.8%) had a childhood-onset BD (before 12 years of age) and 56 (41.2%) had an
adolescents-onset BD. Compared with the adolescent-onset BD, patients with
childhood-onset were more frequently males and had a more frequent co-morbidity
with attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant
disorder (ODD). An episodic course was found in only 42.5% of bipolar children,
but 76.8% of youngsters with adolescent-onset BD. Severity, 6-month treatment
outcome, prevalent mood (elated versus irritable), and co-morbid anxiety did not
differentiate the two groups. CONCLUSIONS: Our findings suggest that a very early
age at onset may identify a form of BD with a more frequent subcontinuous course
and a heavy co-morbidity with ADHD.
PMID: 17201612 [PubMed – indexed for MEDLINE]
Bipolar Disord. 2006 Dec;8(6):710-20.
Co-occurrence of bipolar and attention-deficit hyperactivity disorders in
Singh MK, DelBello MP, Kowatch RA, Strakowski SM.
Division of Bipolar Disorders Research, Department of Psychiatry, University of
Cincinnati College of Medicine, 231 Bethesda Avenue, Cincinnati, OH 45267, USA.
OBJECTIVES: Pediatric bipolar disorder (BPD) and attention-deficit hyperactivity
disorder (ADHD) co-occur more frequently than expected by chance. In this review,
we examine 4 potential explanations for the high rate of this common
co-occurrence: (i) BPD symptom expression leads to overdiagnosis of ADHD in BPD
youth; (ii) ADHD is a prodromal or early manifestation of pediatric-onset BPD;
(iii) ADHD and associated factors (e.g., psychostimulants) lead to the onset of
pediatric BPD; and (iv) ADHD and BPD share an underlying biological etiology
(i.e., a common familial or genetic risk or underlying neurophysiology). METHODS:
Peer-reviewed publications of studies of children and adolescents with comorbid
BPD and ADHD were reviewed. RESULTS: There is a bidirectional overlap between BPD
and ADHD in youth, with high rates of ADHD present in children with BPD (up to
85%), and elevated rates of BPD in children with ADHD (up to 22%).
Phenomenologic, genetic, family, neuroimaging, and treatment studies revealed
that BPD and ADHD have both common and distinct characteristics. While there are
data to support all 4 explanations postulated in this paper, the literature most
strongly suggests that ADHD symptoms represent a prodromal or early manifestation
of pediatric-onset BPD in certain at-risk individuals. Bipolar disorder with
comorbid ADHD may thus represent a developmentally specific phenotype of
early-onset BPD. CONCLUSIONS: The etiology of comorbid BPD and ADHD is likely
multifactorial. Additional longitudinal and biological studies are warranted to
clarify the relationships between BPD and ADHD since they may have important
diagnostic and treatment implications.
PMID: 17156157 [PubMed – indexed for MEDLINE]
Bipolar Disord. 2006 Dec;8(6):696-709.
Pharmacological treatment of psychiatric comorbidity in bipolar disorder: a
review of controlled trials.
Singh JB, Zarate CA Jr.
Mood and Anxiety Disorders Research Program, National Institute of Mental Health,
10 Center Drive, Bethesda, MD 20892, USA.
OBJECTIVE: Little is known about the treatment of psychiatric comorbidities in
bipolar disorder. The aim of this review was to summarize the literature on
controlled pharmacological trials that have been conducted in psychiatric
conditions that commonly co-occur in bipolar disorder. METHODS: A Medline search
(1980-October 2005) using the terms bipolar disorder and randomized controlled
trials, comorbidity, anxiety disorders, alcohol abuse or dependence, substance
abuse or dependence, eating disorder, impulse control disorders,
attention-deficit disorder, lithium, anticonvulsants, atypical antipsychotic
drugs, antidepressants, stimulants was used. RESULTS: The literature establishes
a strong association between bipolar disorder and substance abuse/dependence,
anxiety disorders, impulse control disorders, eating disorders and
attention-deficit hyperactivity disorder. Comorbidity often complicates the
diagnosis and the treatment of bipolar disorder and worsens its course of illness
and prognosis. Few controlled pharmacological studies have examined the treatment
of comorbid conditions in patients with bipolar disorder. CONCLUSIONS: Treatment
of psychiatric comorbidities in bipolar disorder is not based on controlled data
but is largely empirically based. Controlled trials in patients with bipolar
disorder and comorbidity are urgently needed.
PMID: 17156156 [PubMed – indexed for MEDLINE]
Psychiatry Res. 2006 Dec 7;145(2-3):155-67. Epub 2006 Nov 1.
Psychopathology in the young offspring of parents with bipolar disorder: a
controlled pilot study.
Hirshfeld-Becker DR, Biederman J, Henin A, Faraone SV, Dowd ST, De Petrillo LA,
Markowitz SM, Rosenbaum JF.
Pediatric Psychopharmacology Program, Massachusetts General Hospital, 185 Alewife
Brook Parkway, Suite 2100, Cambridge, MA 02138, USA. firstname.lastname@example.org
Studies have suggested that the offspring of parents with bipolar disorder are at
risk for a spectrum of psychopathology, but few have focused on children in the
youngest age ranges or examined the impact of comorbid parental disorders. We
utilized a pre-existing sample of young (mean age: 6.8 years) offspring of
parents with bipolar disorder (n=34), of parents with panic or major depression
(n=179), and of parents with neither mood or anxiety disorder (n=95). Children
were assessed blindly to parental diagnoses using the Schedule for Affective
Disorders and Schizophrenia-Epidemiologic version (K-SADS-E). Offspring of
bipolar parents had significantly higher rates of disruptive behavior and anxiety
disorders than offspring from both of the comparison groups, accounted for by
elevated rates of ADHD and overanxious disorder. These comparisons were
significant even when lifetime histories of the corresponding categories of
comorbid disorders in the parents (disruptive behavior disorders and anxiety
disorders) were covaried. In addition, offspring of bipolar parents had increased
rates of bipolar I disorder, compared with psychiatric controls. Results support
the hypotheses of elevated behavior, anxiety, and mood disorders among offspring
at risk for bipolar disorder, and suggest that this psychopathology is already
evident in early childhood.
PMID: 17083985 [PubMed – indexed for MEDLINE]
Dev Psychopathol. 2006 Fall;18(4):939-69.
Phenomenology and diagnosis of bipolar disorder in children, adolescents, and
adults: complexities and developmental issues.
Carlson GA, Meyer SE.
State University of New York, Stony Brook, NY 11794-8790, USA.
This review addresses the phenomenology of mania/bipolar disorder from a
developmental psychopathology perspective and uses cases with longitudinal
information to illustrate major points. Beginning with a summary of the
phenomenology of bipolar illness as it occurs in adults, the authors identify
diagnostic complexities unique to children and adolescents. These include the
challenges of characterizing elation and grandiosity; differentiating mania from
comorbid symptoms, rages, sequelae of maltreatment, and typical developmental
phenomena; and the unique manifestations of psychosis. We conclude with the
observation that a significant difference between early and later onset bipolar
disorder is that, in the former, there appears to be a global delay or arrest in
the development of appropriate affect regulation; whereas in adult-onset bipolar
illness, emotion dysregulation generally presents as an intermittent phenomenon.
At this juncture, the study of childhood bipolar illness would benefit from a
developmental psychopathology perspective to move beyond the level of
cross-sectional symptom description to begin to study individuals over time,
focusing on developmental, environmental, genetic, and neurobiological influences
on manifest behavior.
PMID: 17064424 [PubMed – indexed for MEDLINE]
J Affect Disord. 2007 Apr;99(1-3):51-7. Epub 2006 Oct 12.
Childhood antecedent disorders to bipolar disorder in adults: a controlled study.
Henin A, Biederman J, Mick E, Hirshfeld-Becker DR, Sachs GS, Wu Y, Yan L, Ogutha
J, Nierenberg AA.
Pediatric Psychopharmacology Unit and Bipolar Clinic and Research Program,
Massachusetts General Hospital and Harvard Medical School, Boston, MA 02138,
United States. email@example.com
OBJECTIVE: The aim of the study was to examine antecedent childhood psychiatric
disorders in adult patients with bipolar disorder. METHOD: Using structured
diagnostic interviews, childhood psychiatric diagnoses of 83 referred patients
with diagnosed DSM-IV bipolar disorder were compared to those of 308 adults
without mood disorders. RESULTS: Patients with bipolar disorder had significantly
higher rates of childhood disruptive behavior disorders (ADHD,
oppositional-defiant disorder, and conduct disorder), childhood anxiety disorders
(separation anxiety and overanxious disorder), and enuresis, compared to patients
without mood disorders. The presence of these childhood disorders was associated
with an earlier age of onset of bipolar illness. LIMITATIONS: The retrospective
nature of the study may have affected both the rates of disorders recalled, as
well as the ages of onset of disorders. Different referral sources for bipolar
and comparison participants may have also impacted findings. CONCLUSIONS: Bipolar
disorder in adults is frequently preceded by childhood disruptive behavior and
anxiety disorders. These childhood disorders may be important markers of risk for
adult bipolar disorder.
PMID: 17045657 [PubMed – indexed for MEDLINE]
Clin Pediatr (Phila). 2006 Nov;45(9):801-8.
Diagnosis and management of childhood bipolar disorder in the primary care
Faust DS, Walker D, Sands M.
Department of Psychology, Children’s Hospital, New Orleans, LA 70118, USA.
Early-onset bipolar disorder (BD) is often misdiagnosed and inadequately treated
because of the varying constellation of symptoms that occur across different
developmental stages, the variety of disorders with similar presentation, and the
frequent comorbidities. The etiology of BD is complex, but research confirms the
major role that genetics and environment play in its development. The
pediatrician initially identifies most cases, with subsequent referral to mental
health providers. A complex case involving a child initially diagnosed with
attention deficit hyperactivity disorder (ADHD) and later found to have comorbid
childhood BD is considered, illustrating diagnostic considerations and
appropriate behavioral and psychopharmacological intervention.
PMID: 17041167 [PubMed – indexed for MEDLINE]
33: J Clin Psychiatry. 2006;67 Suppl 11:8-11.
Illness course, comorbidity, gender, and suicidality in patients with bipolar
Department of Psychiatry, Outpatient Program, University of Pennsylvania, PA,
Among patients with bipolar disorder, comorbid conditions are common. Comorbidity
is associated with a more difficult course of illness (such as longer episodes,
shorter time euthymic, and earlier age at onset) and an increase in related
problems (such as suicidality and violence). Data from the Systematic Treatment
Enhancement Program for Bipolar Disorder (STEP-BD) reveal that anxiety disorders,
attention-deficit/hyperactivity disorder, and substance and alcohol use disorder
are conditions that commonly co-occur with bipolar disorder. This article details
these findings and discusses the complications associated with these comorbid
conditions. STEP-BD data about gender differences are also discussed, and
correlates of suicidal ideation among patients entering the program are
PMID: 17029490 [PubMed – indexed for MEDLINE]
Arch Gen Psychiatry. 2006 Oct;63(10):1130-8.
Evid Based Ment Health. 2007 May;10(2):63.
Controlled, blindly rated, direct-interview family study of a prepubertal and
early-adolescent bipolar I disorder phenotype: morbid risk, age at onset, and
Geller B, Tillman R, Bolhofner K, Zimerman B, Strauss NA, Kaufmann P.
Department of Psychiatry, Washington University in St Louis, St Louis, MO
63110-1093, USA. firstname.lastname@example.org
CONTEXT: A key question is whether a prepubertal and early-adolescent bipolar I
disorder phenotype (PEA-BP-I) is the same illness as adult BP-I. This question
arises because of the greater severity, longer current episode duration,
preponderance of mania, and high rates of ultradian rapid cycling and comorbid
attention-deficit/hyperactivity disorder (ADHD) in PEA-BP-I. OBJECTIVES: To
examine morbid risk (MR) of BP-I in first-degree relatives of PEA-BP-I, ADHD, and
healthy control probands, as well as imprinting, sibling recurrence risk, and
anticipation. DESIGN: Controlled, blind direct interview. There were no family
psychopathology exclusions for any proband group. SETTING: University medical
school research unit. PARTICIPANTS: First-degree relatives 6 years and older (n =
690) of 219 probands (95 with PEA-BP-I, 47 with ADHD, and 77 healthy controls).
The PEA-BP-I and ADHD probands were obtained by consecutive new case
ascertainment, and healthy controls were from a random survey; proband diagnoses
were validated via 4-year prospective follow-up. The PEA-BP-I probands had a mean
+/- SD age of 10.8 +/- 2.6 years.Main Outcome Measure Morbid risk. RESULTS: The
MR of BP-I was higher in relatives of PEA-BP-I probands compared with ADHD or
healthy controls (P<.001 for both); the MR in relatives of ADHD and healthy
controls was similar. The MR of BP-I in relatives with ADHD was higher (P<.001)
and age at onset of BP-I was younger in parents with ADHD than in those without
(P<.001). The MR of BP-I in relatives with oppositional, conduct, or antisocial
disorders was higher than in those without (P<.001). Anticipation was evidenced
by a younger age at onset of BP-I in probands than in their parents (P<.001). No
imprinting was found. CONCLUSIONS: Findings support that PEA-BP-I and adult BP-I
are the same diathesis, 7 to 8x greater familiality in child vs adult BP-I, and
family study validation of PEA-BP-I, including its differentiation from ADHD.
PMID: 17015815 [PubMed – indexed for MEDLINE]
J Child Adolesc Psychopharmacol. 2006 Aug;16(4):456-66.
Chronic versus episodic irritability in youth: a community-based, longitudinal
study of clinical and diagnostic associations.
Leibenluft E, Cohen P, Gorrindo T, Brook JS, Pine DS.
Mood and Anxiety Program, National Institute of Mental Health, National
Institutes of Health, Department of Health and Human Services, Bethesda,
Maryland, USA. LEIBS@MAIL.NIH.GOV
OBJECTIVE: Irritability is both a normal developmental phenomenon and a common
psychiatric symptom in children. In psychiatric nosology, a distinction is made
between chronic and episodic irritability. This study examines the validity of
this distinction. METHODS: A sample of 776 youths received Diagnostic and
Statistical Manual of Mental Disorders (DSM)-based structured interviews at three
time points. Questions regarding episodic and chronic irritability were used to
create scales measuring these constructs; associations with age, gender, and
diagnosis were examined. RESULTS: Episodic and chronic irritability differed in
their associations with age. The longitudinal stability within irritability type
was stronger than between types. In longitudinal analyses, chronic irritability
at time 1 (mean age 13.8 +/- 2.6 years) predicted attention deficit/
hyperactivity disorder at time 2 (mean age 16.2 +/- 2.8 years) and major
depression at time 3 (mean age 22.1 +/- 2.7 years). Episodic irritability at time
1 predicted simple phobia and mania at time 2. CONCLUSIONS: Episodic and chronic
irritability in adolescents appear to be stable, distinct constructs. Further
research is needed to elucidate the longitudinal associations of each with
specific psychiatric diagnoses.
PMID: 16958570 [PubMed – indexed for MEDLINE]
Biol Psychiatry. 2007 Jul 15;62(2):115-20. Epub 2006 Sep 1.
Does the Child Behavior Checklist juvenile bipolar disorder phenotype identify
Volk HE, Todd RD.
Doctoral Program in Public Health Studies, Saint Louis University School of
Public Health, Saint Louis, Missouri 63110, USA.
BACKGROUND: A profile of Child Behavior Checklist(CBCL) T-scores>or=70 on the
attention problems, aggression, and anxious/depressed subscales has been proposed
to identify juvenile bipolar disorder(JBD). We tested this hypothesis in a
population-based sample. METHODS: Data for this analysis come from a
birth-records-based twin sample having semi-structured interview and CBCL data
(N=1,346). We compared prevalence of DSM-IV psychiatric disorders and suicidal
behaviors in CBCL-JBD and non-CBCL-JBD subjects. Twin modeling assessed genetic
and environmental contributions to CBCL-JBD. Associations with DRD4 and DAT1 were
examined using chi-square tests. RESULTS: The prevalence of CBCL-JBD was 2.5%. No
subjects with CBCL-JBD met criteria for bipolar or other mood disorders. CBCL-JBD
subjects had more oppositional defiant disorder (ODD), conduct disorder(CD), and
attention deficit hyperactivity disorder(ADHD). The CBCL-JBD profile was uncommon
in these disorders. CBCL-JBD subjects more frequently endorsed suicidal
behaviors. The CBCL-JBD profile was heritable and associated with the number of
DAT1 9-repeat 3′ untranslated region alleles. CONCLUSIONS: The CBCL-JBD phenotype
does not correspond with a semi-structured interview assessment of JBD. ADHD, CD,
and ODD are common in children with CBCL-JBD but do not account for the profile.
Increased suicidal behaviors indicate substantial impairment in CBCL-JBD
PMID: 16950211 [PubMed – indexed for MEDLINE]
Bipolar Disord. 2006 Aug;8(4):373-81.
Attention-deficit hyperactivity disorder — bipolar comorbidity in children and
Masi G, Perugi G, Toni C, Millepiedi S, Mucci M, Bertini N, Pfanner C.
IRCCS Stella Maris, Scientific Institute of Child Neurology and Psychiatry,
Calambrone, Pisa, Italy. email@example.com
OBJECTIVE: A substantial portion of juvenile bipolar disorder (BD) has a comorbid
attention-deficit hyperactivity disorder (ADHD). The aim of our study was to
analyze the cross-sectional and longitudinal implications of such comorbidity in
children and adolescents with BD. METHODS: Ninety-eight refereed patients (mean
age 13.7 +/- 3.0 years) with a diagnosis of BD by the Schedule for Affective
Disorders and Schizophrenia for School-Age Children, Present and Lifetime version
(K-SADS-PL) were followed for 6 months. RESULTS: Thirty-seven BD patients (37.8%)
presented a lifetime diagnosis of comorbid ADHD. The mean age of onset of ADHD
was 3.7 +/- 1.1 years, and the mean age of onset of BD was 10.0 +/- 3.2 years.
Bipolar subjects with comorbid ADHD were predominantly male, younger, and had an
earlier onset of BD (8.1 +/- 2.8 versus 11.1 +/- 2.9 years). Bipolar-ADHD
patients presented more frequently a chronic rather than an episodic course of
BD, with an irritable rather than an elated mood. They showed higher rates of
oppositional defiant disorder/conduct disorder, lower rates of panic disorder,
and less frequently received antidepressant medications. Finally, ADHD
comorbidity was associated with a greater psychosocial impairment. CONCLUSIONS:
ADHD comorbidity is frequent in juvenile BD and can influence age of onset,
phenomenology, comorbidity, and course of BD. A timely diagnosis should improve
our efforts regarding the outcome of these subjects.
PMID: 16879138 [PubMed – indexed for MEDLINE]
J Affect Disord. 2007 Jan;97(1-3):51-9. Epub 2006 Jul 5.
Clinical characteristics of bipolar disorder in very young children.
Danielyan A, Pathak S, Kowatch RA, Arszman SP, Johns ES.
Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, D-3014,
Cincinnati, OH 45229, United States. firstname.lastname@example.org
BACKGROUND: Clinical information about bipolar disorder (BPD) in preschool-age
(3-7 years old) children is extremely limited. This study examined clinical
presentations, applicability of the DSM-IV diagnostic criteria, comorbidity,
recovery and relapse rates, as well as some treatment strategies used in the
management of BPD in preschoolers. METHODS: The charts of 26 outpatient children,
ages 3-7, refereed to a child psychiatry outpatient clinic with mood and
behavioral symptoms, were retrospectively reviewed. RESULTS: The majority of the
patients were referred with the tentative diagnosis of ADHD but the most common
diagnoses made by child and adolescent psychiatrists at the time of initial
evaluation were BPD NOS (61.5%), followed by BPD I (26.9%), and mood disorder NOS
(23.1%). Thirty-eight percent of the patients had one or more comorbid diagnoses.
The most common presenting symptoms were irritability (84.6%) and aggression
(88.5%). The most widely prescribed class of medications after diagnosis in the
clinic was atypical antipsychotics and mood stabilizers. Twenty-six percent of
the patients were treated with a combination of atypical antipsychotics and mood
stabilizers. LIMITATIONS: Retrospective design; small sample size; lack of a
comparison group. CONCLUSIONS: The course of BPD with onset in preschool years is
complicated with high recovery and relapse rates. The questions of development of
age-appropriate diagnostic criteria, long-term prognosis and treatment strategies
used in this population require further intensive investigation.
PMID: 16822549 [PubMed – indexed for MEDLINE]
J Child Adolesc Psychopharmacol. 2006 Jun;16(3):365-70.
Concomitant use of atomoxetine and OROS-methylphenidate in a 10-year-old child
suffering from attention-deficit/hyperactivity disorder with comorbid bipolar
disorder and Tourette syndrome.
Jaworowski S, Benarroch F, Gross-Tsur V.
Department of Liaison Consultation Psychiatry, Shaare Zedek Medical Centre,
Jerusalem, Israel 91031. email@example.com
Atomoxetine and OROS methylphenidate were successfully used concomitantly in a
10-year-old boy suffering from attention-deficit/hyperactivity disorder (ADHD)
with comorbid bipolar disorder and Tourette syndrome (TS). The child received
valproic acid, clonidine, and ziprasidone concurrently. Because possible side
effects of pharmacological treatment for one diagnosis may exacerbate a comorbid
condition, contingent management strategies, when using polypharmacy, are
PMID: 16768644 [PubMed – indexed for MEDLINE]
J Psychiatr Pract. 2006 Mar;12(2):124-7.
Underdiagnosis of bipolar disorder in men with substance use disorder.
Albanese MJ, Clodfelter RC Jr, Pardo TB, Ghaemi SN.
Harvard Medical School and Cambridge Health Alliance, MA 02143, USA.
OBJECTIVE: Recent reports indicate that bipolar disorder is frequently
underdiagnosed in the clinical population, leading to overuse of antidepressants
and underuse of mood stabilizers. This study assessed rates of diagnosis of
bipolar disorder in a substance abuse population. METHOD: The study involved a
retrospective chart review of data from 295 patients admitted to an inpatient
substance abuse program for men. Data were then analyzed from the 85 patients in
the sample who were diagnosed as meeting DSM-IV criteria for bipolar disorder on
intake into the program. Charts were reviewed for relevant clinical and
demographic data. The primary outcome measure was the rate of previous
misdiagnosis. RESULTS: Of the 85 patients diagnosed with bipolar disorder upon
intake, 42 (49%) had not been previously diagnosed with bipolar disorder; of
these 42, 6 (14%) patients had not been assessed previously, while 36 (86%) had
been assessed previously and had received many other psychiatric diagnoses,
including major depression (77%), attention-deficit/hyperactivity disorder (20%),
and panic disorder (3%). Among the comorbid substance use disorders in these
patients, alcohol dependence was the most common (62%), followed by cocaine
(38%), opioid (26%), polysubstance (12%), and sedative-hypnotic (2%) dependence.
Other comorbid Axis I disorders included posttraumatic stress disorder (14%),
attention-deficit/hyperactivity disorder (10%), panic disorder (2%), and
generalized anxiety disorder (2%). CONCLUSION: This study found that bipolar
disorder had not been previously diagnosed in approximately 50% of a sample of
Caucasian males in a substance abuse population who were diagnosed with bipolar
disorder upon admission to an inpatient substance abuse program.
PMID: 16728911 [PubMed – indexed for MEDLINE]
Bipolar Disord. 2006 Apr;8(2):182-7.
Comorbidity of attention deficit hyperactivity disorder in juvenile bipolar
Jaideep T, Reddy YC, Srinath S.
Department of Psychiatry, National Institute of Mental Health and Neurosciences
(NIMHANS), Bangalore, India.
OBJECTIVE: There is some evidence to suggest that attention deficit hyperactivity
disorder (ADHD) and juvenile bipolar disorder could be related. This is based on
studies of comorbidity and some preliminary family study data. However, doubts
continue to be raised about the relationship between the two disorders. This
study examined the comorbidity of disruptive behavior disorders (DBD) that
include ADHD, oppositional defiant disorder (ODD) and conduct disorder (CD) in
juvenile bipolar disorder. METHOD: Seventy-three subjects with onset of bipolar
disorder at age 18 years or younger were evaluated using structured interviews
(Missouri Assessment of Genetics Interview for Children, Structured Clinical
Interview for DSM-IV Axis I disorders–Clinician Version, and Operational
Criteria Checklist for Psychotic Disorders version 3.4). Information was
collected from subjects as well as from their parents. Patients with comorbid DBD
were compared with patients without DBD. RESULTS: Ten subjects (14%) had one or
more comorbid DBD. ADHD, CD, and ODD were present in three (4%), two (3%), and
eight (11%) subjects, respectively. Those with DBD had earlier onset of bipolar
disorder and spent more time ill compared to those without DBD. CONCLUSIONS: The
rates of comorbid DBD in juvenile bipolar disorder are low. The study does not
support a definite relationship between ADHD and juvenile bipolar disorder.
Higher rates reported previously may be due to differing methods of subject
ascertainment. Samples recruited from community and general psychiatric settings
may help to clarify the relationship between bipolar disorder and ADHD.
PMID: 16542189 [PubMed – indexed for MEDLINE]
Psychiatr Hung. 2005;20(4):293-8.[Comorbidity in child psychiatry: is the comorbidity of pediatric mania and ADHD
really that high?] [Article in Hungarian]
BalÃ¡zs J, GÃ¡doros J.
Vadaskert Gyermekpszichiatriai Korhaz es Szakambulancia; Beregszasz u. 145,
Budapest, 1112 Hungary. firstname.lastname@example.org
OBJECTIVE: The purpose of our study was to investigate possible reasons of
diagnosing comorbidity in child psychiatric disorders, with special attention to
the comorbidity of mania and attention deficit-hyperactivity syndrome (ADHD).
METHOD: Using a structured interview, the Mini International Neuropsychiatric
Interview Kid (M.I.N.I. Kid) we examined 112 consecutive admitted children aged
under 18 in the Vadaskert Children’s Psychiatric Hospital. For all children,
best-estimated diagnoses were made by an independent child-psychiatrist as well,
who was blind to the diagnoses of the M.I.N.I. Kid. Six children were diagnosed
as having pervasive developmental disorder by the independent clinician, their
data were excluded. In this way the data of 106 children were included in the
statistical analysis. RESULTS: Comorbidity: Based on the M.I.N.I. Kid test
comorbid diagnoses were found in 74.53% of the children and 51.90% of the
children with comorbid diagnoses had three or more concomitant diagnoses. The
maximum number of diagnoses obtained concomitantly by the M.I.N.I. Kid was 9. The
M.I.N.I. Kid produced 2.58 diagnoses for one child on average. The independent
child-psychiatrist found comorbid diagnoses in 25.47% of the children. The
maximum number of diagnoses made by the independent child-psychiatrist for 1
child was 2. The independent child-psychiatrist established 1.25 diagnoses for
one child on average. Manic/hypomanic episode: Based on the M.I.N.I. Kid manic
episode was diagnosed in 14.15% of the children and hypomanic episode in 6,60% of
them, while the independent psychiatrist did not diagnose these conditions in any
of the children. 99.33% of the children with manic episode were diagnosed
together with ADHD by the M.I.N.I. Kid. In 57.14% of those cases, where the
M.I.N.I. Kid diagnosed a hypomanic episode, it found an ADHD at the same time.
The independent psychiatrist found ADHD in 73.33% of the children with the
diagnoses of manic episode and in 57.14% of the children with hypomanic episode
determined by the M.I.N.I. Kid. CONCLUSIONS: The considerable differences found
in the number of diagnoses made by using the M.I.N.I. Kid and by the independent
child psychiatrist may indicate the possible over-sensitivity of structured
interviews and the characteristics of diagnostic systems: several disorders have
overlapping symptoms, making the differential diagnoses difficult.
PMID: 16462006 [PubMed – indexed for MEDLINE]
Am J Psychiatry. 2006 Feb;163(2):316-8.
Am J Psychiatry. 2007 Jan;164(1):175.
Differences in brain chemistry in children and adolescents with attention deficit
hyperactivity disorder with and without comorbid bipolar disorder: a proton
magnetic resonance spectroscopy study.
Moore CM, Biederman J, Wozniak J, Mick E, Aleardi M, Wardrop M, Dougherty M,
Harpold T, Hammerness P, Randall E, Renshaw PF.
Brain Imaging Center, McLean Hospital, Belmont, MA 02478, USA.
OBJECTIVE: The authors’ goal was to investigate phosphatidylinositol and
glutamatergic metabolism in the anterior cingulate cortex of children and
adolescents with attention deficit hyperactivity disorder (ADHD) alone, children
with ADHD plus bipolar disorder, and children with no axis I diagnosis. METHOD:
Proton spectra were acquired from a 4.8-ml voxel placed in the anterior cingulate
cortex of 30 subjects who were 6 to 13 years old. Fifteen subjects had ADHD and
no comorbid disorder, eight had ADHD plus bipolar disorder, and seven were
healthy comparison subjects. RESULTS: Children with ADHD had a significantly
higher ratio of glutamate plus glutamine to myo-inositol-containing compounds
than children with ADHD plus bipolar disorder and healthy children. CONCLUSIONS:
myo-Inositol-containing compounds may provide information on the action of
antimanic treatments such as lithium, valproate, and carbamazepine. Glutamate and
glutamine are measures of glutamatergic neurotransmission and thus may also
reflect changes in serotonin and dopamine pathways.
PMID: 16449488 [PubMed – indexed for MEDLINE]
Am J Psychiatry. 2006 Feb;163(2):286-93.
Neurocognitive function in unmedicated manic and medicated euthymic pediatric
Pavuluri MN, Schenkel LS, Aryal S, Harral EM, Hill SK, Herbener ES, Sweeney JA.
Center for Cognitive Medicine, Department of Psychiatry, University of Illinois
at Chicago, 912 South Wood St. (M/C 913), Chicago, IL 60612, USA.
OBJECTIVE: A systematic evaluation of neuropsychological functioning in
individuals with pediatric bipolar disorder is necessary to clarify the types of
cognitive deficits that are associated with acutely ill and euthymic phases of
the disorder and the effects of medication on these deficits. METHOD: Unmedicated
(N=28) and medicated (N=28) pediatric bipolar patients and healthy individuals
(N=28) (mean age=11.74 years, SD=2.99) completed cognitive testing. Groups were
matched on age, sex, race, parental socioeconomic status, general intelligence,
and single-word reading ability. A computerized neurocognitive battery and
standardized neuropsychological tests were administered to assess attention,
executive function, working memory, verbal memory, visual memory, visuospatial
perception, and motor skills. RESULTS: Subjects with pediatric bipolar disorder,
regardless of medication and illness status, showed impairments in the domains of
attention, executive functioning, working memory, and verbal learning compared to
healthy individuals. Also, bipolar subjects with comorbid attention deficit
hyperactivity disorder (ADHD) performed worse on tasks assessing attention and
executive function than patients with bipolar disorder alone. CONCLUSIONS: The
absence of differences in the deficits of neurocognitive profiles between acutely
ill unmedicated patients and euthymic medicated patients suggests that these
impairments are trait-like characteristics of pediatric bipolar disorder. The
cognitive deficits found in individuals with pediatric bipolar disorder suggest
significant involvement of frontal lobe systems supporting working memory and
mesial temporal lobe systems supporting verbal memory, regardless of ADHD
PMID: 16449483 [PubMed – indexed for MEDLINE]
Tidsskr Nor Laegeforen. 2006 Jan 26;126(3):302-4.[Bipolar disorders in children and adolescents] [Article in Norwegian]
Udal AH, GrÃ¸holt B.
Barne- og ungdomspsykiatrisk avdeling, SÃ¸rlandet sykehus, 4809 Arendal.
BACKGROUND: Bipolar disorders often develop in children and adolescents but are
seldom diagnosed before adulthood. These illnesses are associated with
considerable morbidity and mortality. The aim of this paper is to provide
knowledge to facilitate earlier diagnosis. MATERIAL AND METHOD: Medline search.
RESULTS: Bipolar disorders are characterised by serious fluctuations in energy
and mood. The diagnosis of bipolar disorders in children and adolescents is
challenging because the clinical presentation is influenced by ongoing neural
development, which cause considerable symptom overlap and comorbidity with ADHD,
conduct disorders, anxiety and Tourette’s syndrome. ADHD symptoms may be a
precursor of bipolar disorder among some of the youngest children, and
prepubertal depression is often pre-bipolar.
PMID: 16440034 [PubMed – indexed for MEDLINE]
Appl Neuropsychol. 2005;12(2):77-82.
Incidence of ADHD in adults with severe mental health problems.
Kennemer K, Goldstein S.
Neurology, Learning and Behavior Center, Salt Lake City, Utah 84102-2015, USA.
The purpose of this study was to determine the prevalence rates of attention
deficit hyperactivity disorder (ADHD) and comorbid disorders in an adult
inpatient psychiatric setting. Patient charts were reviewed from a state
hospital in the western United States. Of the 292 persons served in 2002, only 6
received a diagnosis of ADHD. Of these patients, 2 received additional diagnoses
for Major Depression, 1 for General Anxiety and 1 for Bipolar Disorder. Five of
the 6 ADHD participants had a history of substance abuse and 4 were diagnosed
with Personality Disorders. None of the 6 diagnosed with ADHD received a
diagnosis of Learning Disability. A variety of nonstimulant medications were
utilized to treat these patients. Characteristics of adult psychiatric
populations are reviewed. Prevalence, comorbidity and implications for future
research regarding adult ADHD are discussed.
PMID: 16083396 [PubMed – indexed for MEDLINE]
Comorbidities and costs of adult patients diagnosed with attention-deficit
Secnik K, Swensen A, Lage MJ.
Lilly Research Laboratories, Indianapolis, Indiana, USA.
INTRODUCTION: The purpose of this retrospective study was to examine the
prevalence of comorbidities, resource use, direct medical costs, and the costs
associated with missed work for adults diagnosed with attention-deficit
hyperactivity disorder (ADHD). STUDY DESIGN: From a large claims database that
captures inpatient, outpatient and prescription drug services, individuals
diagnosed with ADHD between the years 1999 and 2001 were retrospectively
identified. The ADHD cohort (n = 2252) were matched with a non-ADHD cohort (n =
2252) on a 1 : 1 ratio, based upon age, gender, metropolitan statistical area
and type of insurance coverage. The ADHD cohort was compared with the non-ADHD
cohort for differences in comorbidities and direct medical costs (inpatient,
outpatient and prescription drug costs) using year 2001 prices. Using data from
six Fortune 200 employers, time missed from work and costs associated with
absenteeism, short-term disability and worker’s compensation was examined for a
subsample (n = 354) of the employees diagnosed with ADHD. Chi-square and
t-statistics were used to compare the ADHD population with the control group
with regards to comorbidites and service use. Analysis of covariance and
multivariate regressions were used to examine differences in days missed from
work, direct medical costs and costs associated with missed work. RESULTS:
Adults diagnosed with ADHD were significantly more likely to have a comorbid
diagnosis of asthma (p = 0.0014), anxiety (p < 0.0001), bipolar disorder (p <
0.0001), depression (p < 0.0001), drug or alcohol abuse (p < 0.0001), antisocial
disorder (p = 0.0081) or oppositional disorder (p = 0.0022) compared with the
control group. Controlling for the impact of comorbidities, adults diagnosed
with ADHD had significantly higher outpatient costs (USD 3009 vs USD 1492; p <
0.0001), inpatient costs (USD 1259 vs USD 514; p < 0.0001), prescription drug
costs (USD 1673 vs USD 1008; p < 0.0001), and total medical costs (USD 5651 vs
USD 2771; p < 0.0001) compared with the non-ADHD cohort. Employees diagnosed
with ADHD missed significantly more days due to ‘unofficial’ absences (4.33 days
vs 1.13 days; p < 0.0001). CONCLUSIONS: The results demonstrate that adults
diagnosed with ADHD have a higher prevalence of comorbidities, higher medical
costs and more absences than matched individuals without ADHD. These findings
suggest that there may be an opportunity for the effective treatment of ADHD to
lead to cost-offsets.
PMID: 15693731 [PubMed – indexed for MEDLINE]
J Clin Psychiatry. 2003 Oct;64(10):1170-6; quiz, 1274-6.
Occult mood disorders in 104 consecutively presenting children referred for the
treatment of attention-deficit/hyperactivity disorder in a community mental
Dilsaver SC, Henderson-Fuller S, Akiskal HS.
Rio Grande City Texas Community Mental Health Mental Retardation Clinic, Rio
Grande City, TX, USA. StevenDilsaver@aol.com
OBJECTIVE: To ascertain the prevalence of mood disorders among consecutively
evaluated prepubertal children presenting for the treatment of
attention-deficit/hyperactivity disorder (ADHD) in a community mental health
clinic. METHOD: 104 children received systematic assessments designed to
identify individuals meeting the DSM-IV criteria for major depressive disorder
(MDD), mania, and ADHD. “Standard” and “modified” criteria for mania were
employed. Modified criteria, in an effort to minimize false-positive diagnoses
of mania, required the presence of euphoria and/or flight of ideas. A child
meeting the criteria for MDD or either set of criteria for mania was categorized
as having a mood disorder. Mood disorders in first-degree relatives were
assessed using a systematic interview. Data were gathered from 2000 to 2002.
RESULTS: Sixty-two children (59.6%) had a mood disorder. Compared with those who
did not have a mood disorder, they were 3.3 times more likely (54.8% vs. 16.7%)
to have a family history of any affective disorder (p <.0001) and 18.3 times
more likely (43.5% vs. 2.4%) to have a family history of bipolar disorder (p
<.0001). Twenty (32.3%) of the children with and none without a mood disorder
had psychotic features (p <.0001). Compared with those meeting only the standard
criteria for mania, those meeting the modified criteria were 9.1 times more
likely (69.8% vs. 7.7%) to have a family history of an affective disorder (p
<.0001) and 7.3 times more likely (55.8% vs. 7.7%) to have a family history of
bipolar disorder (p =.002). CONCLUSION: Children who presumably have ADHD often
have unrecognized affective illness. Our findings support the view that children
meeting the modified criteria for mania have veritable bipolar disorder. These
findings, which were derived in the course of delivering routine clinical
services in a community mental health clinic, are consistent with those obtained
in research settings suggesting that children presenting with ADHD often have
occult mood disorders, especially unrecognized bipolarity. We suggest that
clinicians encountering children with prominent features of ADHD inquire about
the presence of euphoria and flight of ideas. We submit that the presence of
these “classic” manifestations of mania strongly suggests the presence of occult
bipolarity, even if course of illness otherwise markedly deviates from “classic”
PMID: 14658964 [PubMed – indexed for MEDLINE]
Bipolar Disord. 2003 Jun;5(3):217-25.
Bipolar Disord. 2003 Aug;5(4):307.
Combination treatment in bipolar disorder: a review of controlled trials.
Zarate CA Jr, Quiroz JA.
The Mood and Anxiety Disorders Program, National Institute of Mental Health,
Bethesda, MD 20892, USA. email@example.com
OBJECTIVES: Monotherapy is often inadequate and combination drug regimens have
become the norm for the treatment of bipolar disorder. Virtually all classes of
psychotropic drugs have been used in bipolar disorder in combination for a
variety of indications. This article reviews the available published data from
controlled, blinded studies regarding combination treatments in the different
treatment phases of bipolar disorder. METHODS: Articles for this review were
obtained from a search of the Medline database (1966-2002), using the following
keywords and phrases: add-on, antipsychotic, anticonvulsant, antidepressant,
combination treatment, lithium, neuroleptic, and polypharmacy. The search was
augmented by data presented at scientific meetings. Data included in this
article were only from controlled studies that evaluated combinations of two or
more agents. RESULTS: For acute mania, the most useful combination treatments as
determined by controlled studies, appear to be an antipsychotic drug with a
mood-stabilizer. The combination of lithium and valproate, even though widely
used for acute mania, is lacking in controlled data. For acute bipolar
depression, the controlled combination studies reviewed fail to show clear
advantages in efficacy of an antidepressant with a mood-stabilizer versus two
stabilizers or a mood-stabilizer alone. Large, controlled, randomized, long-term
studies with modern antidepressants are not available. Controlled combination
studies of mood-stabilizers suggest gains in efficacy over monotherapy in the
long-term treatment of bipolar disorder. CONCLUSIONS: Controlled combination
studies in bipolar disorder are uncommon. Increased attention should be given to
study combination treatments in all phases of bipolar illness to determine the
most efficacious and safest combinations.
PMID: 12780875 [PubMed – indexed for MEDLINE]
Curr Psychiatry Rep. 2002 Apr;4(2):146-52.
Familial links between attention deficit hyperactivity disorder, conduct
disorder, and bipolar disorder.
Doyle AE, Faraone SV.
Massachusetts General Hospital, 15 Parkman Street, ACC-725, Boston, MA 02114,
Although family, twin, and adoption studies indicate that attention deficit
hyperactivity disorder (ADHD) is a familial condition with a robust genetic
component, molecular genetic studies of candidate genes have produced
inconsistent findings. One of the challenges to elucidating the genetic
architecture of ADHD is its potential genetic heterogeneity. Therefore, efforts
are needed to identify etiologically homogeneous subgroups of subjects with ADHD
for use in genetic studies. The current article reviews evidence suggesting that
parsing ADHD subjects based on comorbidity with conduct and bipolar disorders
may yield familial subtypes that are suitable for genetic analyses.
PMID: 11914177 [PubMed – indexed for MEDLINE]
J Child Adolesc Psychopharmacol. 2002 Spring;12(1):11-25.
DSM-IV mania symptoms in a prepubertal and early adolescent bipolar disorder
phenotype compared to attention-deficit hyperactive and normal controls.
Geller B, Zimerman B, Williams M, Delbello MP, Bolhofner K, Craney JL, Frazier
J, Beringer L, Nickelsburg MJ.
Department of Psychiatry, Washington University School of Medicine, St Louis,
Missouri 63110, USA. firstname.lastname@example.org
OBJECTIVE: To compare the prevalence of Diagnostic and Statistical Manual of
Mental Disorders, 4th edition (DSM-IV) mania symptoms in a prepubertal and early
adolescent bipolar disorder phenotype (PEA-BP) to those with attention deficit
hyperactivity disorder (ADHD) and normal community controls (CC). METHODS: To
optimize generalizeability, subjects with PEA-BP and ADHD were consecutively
ascertained from outpatient pediatric and psychiatric sites, and CC subjects
were obtained from a random survey. All 268 subjects (93 with PEA-BP, 81 with
ADHD, and 94 CC) received comprehensive, blind, baseline research assessments of
mothers about their children and of children about themselves. PEA-BP was
defined by DSM-IV mania with elation and/or grandiosity as one criterion to
ensure that subjects had one of the two cardinal symptoms of mania and to avoid
diagnosing mania only by criteria that overlapped with those for ADHD. RESULTS:
Five symptoms (i.e., elation, grandiosity, flight of ideas/racing thoughts,
decreased need for sleep, and hypersexuality) provided the best discrimination
of PEA-BP subjects from ADHD and CC controls. These five symptoms are also
mania-specific in DSM-IV (i.e., they do not overlap with DSM-IV symptoms for
ADHD). Irritability, hyperactivity, accelerated speech, and distractibility were
very frequent in both PEA-BP and ADHD groups and therefore were not useful for
differential diagnosis. Concurrent elation and irritability occurred in 87.1% of
subjects with PEA-BP. Data on suicidality, psychosis, mixed mania, and
continuous rapid cycling were also provided. CONCLUSION: Unlike late
teenage/adult onset bipolar disorder, even subjects with PEA-BP selected for
DSM-IV mania with cardinal symptoms have high rates of comorbid DSM-IV ADHD.
High rates of concurrent elation and irritability were similar to those in adult
PMID: 12014591 [PubMed – indexed for MEDLINE]
Bipolar Disord. 2001 Dec;3(6):325-34.
Review of studies of child and adolescent offspring of bipolar parents.
DelBello MP, Geller B.
Bipolar and Psychotic Disorders Research Program, Department of Psychiatry,
University of Cincinnati College of Medicine, OH 45267-0559, USA.
OBJECTIVE: The authors reviewed studies of child and adolescent offspring of
bipolar (BP) parents. Findings from these studies are critically discussed with
respect to methodological issues that can inform future designs. METHODS: A
Medline search was performed to identify studies that examined child and
adolescent offspring of BP parents. Publications were excluded if they did not
separate offspring of BP parents from offspring of major depressive disorder or
schizoaffective parents (“affective offspring”) or did not separately analyze
data from child- and adolescent-age versus adult offspring. RESULTS: Seventeen
studies fit these review criteria. Rates of mood disorders in child and
adolescent offspring of BP parents ranged from 5 to 67% compared with rates in
offspring of healthy volunteers of 0-38%. Rates of non-mood disordered
psychopathology ranged from 5 to 52% in offspring of BP parents and from 0 to
25% in offspring of healthy volunteers. Rates of mood disorders and of other
psychopathology were increased in offspring of BP parents compared with
offspring of healthy volunteers in all of the eight studies that included a
comparison group of offspring of healthy volunteers. CONCLUSIONS: Studies
suggest that children (< or =21 years) of BP parents are at increased risk for
developing mood and other disorders (e.g., disruptive, anxiety). Therefore,
additional investigations are clearly warranted. In the context of current
research on diagnosis, assessment, longitudinal course and comorbidity of
childhood mania, the following suggestions for the design of future studies
should be considered: 1) Phenotypic specification of bipolar manifestations
(e.g., BP-I, BP-II, BP-NOS) in child/adolescent offspring and in bipolar parents
themselves. 2) Control groups that are pediatric-age relevant and thus include
attention-deficit hyperactivity disorder. 3) Assessments that include items for
prepubertal mania and for onsets and offsets of all occurrences of symptoms and
of environmental factors (e.g., life events) in offspring and in parents so that
trajectories of overlap and sequence between child and parental mania can be
investigated. 4) These detailed onsets and offsets of symptoms are also
necessary to investigate prodromal manifestations of mania in the offspring. 5)
Unaffected offspring present a unique opportunity to study pre- and postmorbid
cognitive and physiological endophenotypes and structural and functional brain
abnormalities. Findings from offspring studies will be crucial to inform
research on the development of early intervention and prevention strategies.
PMID: 11843782 [PubMed – indexed for MEDLINE]
J Affect Disord. 2001 Dec;67(1-3):159-65.
Measures of attention and hyperactivity symptoms in a high-risk sample of
children of bipolar parents.
Duffy A, Grof P, Kutcher S, Robertson C, Alda M.
Dalhousie University, Department of Psychiatry, Halifax, Nova Scotia, Canada.
BACKGROUND: To determine whether significant symptoms of inattention were
present among the offspring of well-characterized bipolar parents. METHODS: We
included 53 offspring of 30 parents meeting DSM-IV criteria for bipolar disorder
diagnosed by consensus on the basis of a SADS-L interview and a wealth of
longitudinal clinical data. The unaffected parent had no lifetime history of a
major psychiatric illness. Offspring, prospectively followed for up to 5 years,
completed psychometric measures of attention and mood when judged to be at a
good level of functioning (well, remitted or treated). RESULTS: Those offspring
with any lifetime psychiatric diagnosis endorsed more subjective problems with
attention. However, there was no measurable difference on tasks of sustained
attention between those with and those without a lifetime psychiatric illness
including affective disorder. There was a significant association between
self-reported symptoms of depression and inattention, but no association between
either self-report measure and an objective measure of sustained attention.
LIMITATIONS: This study was not intended to be a comprehensive
neuropsychological investigation of at risk offspring. CONCLUSIONS: In this
high-risk population, subjective difficulty with attention appeared to be
state-dependent, associated with the degree of subjective distress related to an
underlying psychiatric illness.
PMID: 11869763 [PubMed – indexed for MEDLINE]
J Child Adolesc Psychopharmacol. 2001 Fall;11(3):301-9.
Gabapentin and methylphenidate treatment of a preadolescent with attention
deficit hyperactivity disorder and bipolar disorder.
Hamrin V, Bailey K.
Yale University, School of Nursing, New Haven, Connecticut 06510, USA.
Gabapentin is an anticonvulsant drug released in the United States in 1993 for
use as adjunctive therapy in refractory partial epilepsy. The mechanism of
action of gabapentin is unknown, but the drug has very favorable
pharmacokinetics and a good safety profile, which allows its use in high-risk
patients. Several reports have described the successful use of gabapentin for
bipolar disorders in adults, but there are no controlled studies in the use of
gabapentin in children and adolescents. We describe a 12-year-old boy with a
history of attention deficient hyperactivity disorder (ADHD), reading disorder,
mixed receptive and expressive language disorder, encopresis, and bipolar
disorder II who was treated with gabapentin 200 mg/day added to methylphenidate
30 mg/day. Within 3 weeks the improvement and stabilization of mood symptoms was
remarkable, as noted by mother, teacher, and clinician, and remained so for 6
months of follow-up. Comorbid bipolar disorder and ADHD is a hotly debated topic
in the child and adolescent psychiatric literature, with rates of comorbid ADHD
and bipolar disorder ranging from 22% to 90%. Controlled studies are needed to
evaluate the possible antimanic mood stabilizing and/or antidepressant
properties or gabapentin in youths.
PMID: 11642481 [PubMed – indexed for MEDLINE]
J Neuropsychiatry Clin Neurosci. 2001 Summer;13(3):385-95.
Impairments of attention and effort among patients with major affective
Cohen R, Lohr I, Paul R, Boland R.
Department of Psychiatry and Human Behavior, Brown University School of
Medicine, Miriam Hospital, Providence, Rhode Island 02906, USA. email@example.com
Impairments of attention are common among people with major affective disorders,
yet the influence of effortful task demands on attentional performance in
unipolar and bipolar illness has been little studied. The authors compared
psychiatric inpatients with primary diagnoses of unipolar or bipolar affective
disorder (n=27) and age-matched normal control subjects (n=20) on a battery of
eight neuropsychological tasks designed to measure different attentional
functions. There were low-effort and high-effort versions of each task.
Significant group differences were consistently observed on tasks demanding
sustained and focused attention, but not on tasks requiring visual selective
attention. Although affective disorder patients showed impairments on most tasks
regardless of level of task effort, group differences were greatest on
high-effort conditions. Results indicate that patients with major affective
disorders show significant attentional impairments on most measures of effortful
attention, and the magnitude of these impairments increases as the effortful
demands of the task increase.
PMID: 11514646 [PubMed – indexed for MEDLINE]
J Paediatr Child Health. 1999 Apr;35(2):199-203.
Confirmation that Child Behavior Checklist clinical scales discriminate juvenile
mania from attention deficit hyperactivity disorder.
Hazell PL, Lewin TJ, Carr VJ.
Child and Youth Mental Health Service, Wallsend Hospital, NSW, Australia.
OBJECTIVE: To determine whether boys meeting diagnostic criteria for juvenile
mania and attention deficit hyperactivity disorder (mania-ADHD) may be
distinguished from boys with ADHD alone on a range of clinical and family
variables. METHODOLOGY: Boys aged 9-13 years with mania-ADHD (n = 25), ADHD
alone (n = 99), or no psychiatric diagnosis (n = 27) were compared on parent and
teacher report Child Behavior Checklists (CBCL) and Conners Questionnaires,
self-report CBCLs, patterns of comorbidity, intellectual functioning, and family
variables. RESULTS: Mania-ADHD subjects had significantly higher mean ratings
than ADHD only subjects on the parent CBCL for the Withdrawn, Thought Problems,
Delinquent Behavior and Aggressive Behavior scales and significantly higher
rates of comorbid depression, anxiety and psychotic symptoms. Other variables
did not distinguish the mania-ADHD and ADHD only groups. CONCLUSIONS: These data
confirm previous research indicating that the CBCL may be used to assist in the
clinical identification of manic children.
PMID: 10365361 [PubMed – indexed for MEDLINE]
J Child Adolesc Psychopharmacol. 1999;9(4):247-56.
Systematic chart review of the pharmacologic treatment of comorbid attention
deficit hyperactivity disorder in youth with bipolar disorder.
Biederman J, Mick E, Prince J, Bostic JQ, Wilens TE, Spencer T, Wozniak J,
Pediatric Psychopharmacology Unit of the Child Psychiatry Service, Massachusetts
General Hospital, Boston, USA. firstname.lastname@example.org
The objective of this study was to evaluate pharmacological approaches for
attention deficit hyperactivity disorder (ADHD) in children with bioplar
disorder and comorbid ADHD. The medical charts of 38 patients with diagnoses of
both Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised
ADHD and bipolar disorder were reviewed over multiple visits to assess
improvement and prescription patterns. Logistic regression was used to model the
probability of improvement at each visit, and robust standard errors were
estimated in order to account for correlation among individuals using Huber’s
correction for clustered data. The proportion of visits at which ADHD symptoms
were rated as improved following initial improvement in manic symptoms was 7.5
times greater than before initial improvement of manic symptoms. The recurrence
of manic symptoms following their initial stabilization significantly inhibited
ADHD response to medication. Although tricyclic antidepressants (TCAs)
significantly increased the probability of ADHD improvement following mood
stabilization, there was also a significant association between treatment with
TCAs and relapse of manic symptoms. Our results support the hypothesis that mood
stabilization is a prerequisite for the successful pharmacologic treatment of
ADHD in children with both ADHD and manic symptoms. Although TCAs can be helpful
in the management of ADHD children with manic symptoms, these drugs should be
used with caution since they can also have a destabilizing effect on manic
Psychiatr Clin North Am. 1998 Dec;21(4):917-26, viii.
Frequently missed diagnoses in adolescent psychiatry.
Department of Psychiatry, University of New Mexico Health Science Center,
Symptom overlap, comorbidity, disagreement among informants, and the impact of
development complicate psychiatric diagnoses in the adolescent patient. This
review of frequently missed diagnoses includes anxiety disorders, ADD without
hyperactivity, early-onset bipolar disorder, syndromes associated with trauma,
and substance abuse.
PMID: 9890130 [PubMed – indexed for MEDLINE]