The Relationship Between Bipolar Disorder and A.D.D.

A MEDLINE Search By, Ivan Goldberg, M.D.

J Child Adolesc Psychopharmacol. 2003 Winter;13(4):531-43. 
 
Temperament and character factors in a prepubertal and early adolescent bipolar
disorder phenotype compared to attention deficit hyperactive and normal
controls.
 
Tillman R, Geller B, Craney JL, Bolhofner K, Williams M, Zimerman B, Frazier J,
Beringer L.
 
Department of Psychiatry, Washington University School of Medicine, St. Louis,
Missouri 63110, USA.
 
OBJECTIVE: To compare temperament and character (T/C) factors in a prepubertal
and early adolescent bipolar disorder phenotype (PEA-BP), attention deficit
hyperactivity disorder (ADHD), and normal community controls (NC). METHODS:
Subjects in PEA-BP (n = 101), ADHD (n = 68), and NC (n = 94) groups were
diagnostically assessed with the Washington University in St. Louis Kiddie
Schedule for Affective Disorders and Schizophrenia given separately to mothers
about their children and to children about themselves. Diagnosis of PEA-BP was
defined as Diagnostic and Statistical Manual of Mental Disorders, fourth
edition, bipolar disorder (manic or mixed phase) with at least one cardinal
symptom of mania (i.e., elation and/or grandiosity) to avoid diagnosing mania by
symptoms that overlapped with those for ADHD. The Junior Temperament and
Character Inventory (JTCI) was used to measure T/C factors. Separate JTCI data
were obtained from mothers about their children and from children about
themselves. RESULTS: Parent- and child-reported novelty seeking were
significantly higher in PEA-BP than in NC subjects. Novelty seeking was
significantly higher in the ADHD group than in the NC group only by parent
report. Parent and/or child report showed PEA-BP and ADHD subjects to be
significantly less reward-dependent, persistent, self-directed, and cooperative
than NC subjects. Parent-reported cooperativeness was significantly lower in
PEA-BP than in ADHD subjects. CONCLUSION: These findings are consistent with
studies of novelty seeking in adults who had either BP or ADHD and are discussed
in relationship to genetic studies of dopamine receptors and novelty seeking.
 
PMID: 14977466 [PubMed - indexed for MEDLINE]
<HR>
J Child Adolesc Psychopharmacol. 2003 Winter;13(4):507-14. 
 
Clinical correlates of episodicity in juvenile mania.
 
Bhangoo RK, Dell ML, Towbin K, Myers FS, Lowe CH, Pine DS, Leibenluft E.
 
The Mood and Anxiety Program, National Institute of Mental Health, National
Institutes of Health, Department of Health and Human Services, Bethesda,
Maryland, USA.
 
OBJECTIVE: Researchers debate whether the diagnostic criteria for mania should
differ between children and adults. Specifically, although the Diagnostic and
Statistical Manual of Mental Disorders (fourth edition; DSM-IV) requires
episodic mood changes, children commonly are diagnosed as manic on the basis of
chronic irritability. In this preliminary study, children carrying a diagnosis
of bipolar disorder (BPD) in the community were classified as having either
episodic or chronic symptoms. We hypothesized that the episodic group would be
more likely to have a history of psychosis and a parental history of BPD,
whereas the chronic group would be more likely to have conduct disorder.
METHODS: Parents of children carrying the BPD diagnosis were interviewed on the
telephone to obtain psychiatric and family histories. Children were considered
episodic (n = 34) if they had a history of one or more DSM-IV manic/hypomanic
episodes meeting full duration criteria and chronic (n = 53) if they had no
discernable episodes. RESULTS: The episodic group was more likely to have had
psychosis, parental history of BPD, and to have experienced each manic symptom
except for irritability and psychomotor agitation. Children in the episodic
group were also more likely to have had a depressive episode meeting full DSM-IV
criteria and were more likely to have made a suicide attempt. Children in the
chronic group were not more likely to meet criteria for conduct disorder but
were more likely to exhibit violence toward others. CONCLUSIONS: These
preliminary data indicate that, among children being treated for BPD in the
community, those with discrete episodes of mania may be more likely to have a
lifetime history of psychosis and a parental history of BPD. The latter
hypothesis should be tested in a sample where relatives are interviewed
directly.
 
PMID: 14977463 [PubMed - indexed for MEDLINE]
<HR>
J Child Adolesc Psychopharmacol. 2003 Winter;13(4):489-94. 
 
Mania in six preschool children.
 
Tumuluru RV, Weller EB, Fristad MA, Weller RA.
 
Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania
15213, USA. tumulururv@upmc.edu
 
At least nine cases of apparent preschool manic-depressive illness have been
previously reported in the literature. In each of these children, a strong
family history of affective illness was noted. In this report, the case
histories of six preschool children ages 3 to 5 years with bipolar illness are
summarized. These six were obtained from a sample of 36 consecutively
hospitalized preschool children. Thus 17% of these hospitalized preschool
children had bipolar illness. All had irritable mood, strong family history of
affective illness, and previous presentation with symptoms of attention deficit
hyperactivity disorder. They were diagnosed following a thorough clinical
interview. Five children were treated with lithium; all five improved. Preschool
mania exists as an identifiable entity and may respond to classic pharmacologic
treatments.
 
Publication Types:
 Case Reports
 
PMID: 14977461 [PubMed - indexed for MEDLINE]
<HR>
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
health clinic.
 
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"
descriptions.
 
PMID: 14658964 [PubMed - indexed for MEDLINE]
<HR>
J Am Acad Child Adolesc Psychiatry. 2003 Dec;42(12):1486-93. 
 
Ages of onset and rates of syndromal and subsyndromal comorbid DSM-IV diagnoses
in a prepubertal and early adolescent bipolar disorder phenotype.
 
Tillman R, Geller B, Bolhofner K, Craney JL, Williams M, Zimerman B.
 
Department of Psychiatry, Washington University School of Medicine, St. Louis,
USA.
 
OBJECTIVE: To study rates and ages of onset of DSM-IV syndromal and subsyndromal
comorbidity in a prepubertal and early adolescent bipolar disorder phenotype
(PEA-BP) (N = 93) compared to attention-deficit/hyperactivity disorder (ADHD) (N
= 81). METHOD: The WASH-U-KSADS was given by raters blinded to subject group
separately to mothers about their children and to children about themselves.
PEA-BP was defined as DSM-IV mania with at least one cardinal symptom of mania
(elation or grandiosity) to avoid diagnosing using only symptoms that overlapped
with those for ADHD. Syndromal diagnoses required a CGAS score of 60 or less to
ensure severity at a level of definite "caseness." RESULTS: PEA-BP subjects were
aged 10.9 (SD = 2.6) at baseline and 6.8 (SD = 3.4) at onset of first mania
episode. Rates of oppositional defiant disorder and total number of
comorbidities were significantly higher in the PEA-BP group than the ADHD group.
In PEA-BP subjects, mean ages of onset of ADHD occurred before the first manic
episode, and obsessive compulsive, oppositional defiant, social phobia,
generalized anxiety, separation anxiety, and conduct disorders occurred after.
CONCLUSIONS: Onsets of ADHD before mania and of oppositional defiant
disorder/conduct disorder after mania have clinical and research implications.
These include the need to examine for mania symptoms in children with ADHD
and/or oppositional defiant disorder/conduct disorder and to develop scales to
differentiate preschool mania from ADHD. Comparison with other studies
demonstrated the importance of DSM system and severity scales in reporting
comorbidity rates.
 
PMID: 14627884 [PubMed - indexed for MEDLINE]
<HR>
Paediatr Drugs. 2003;5(11):741-50. 
 
Psychiatric comorbidities in children with attention deficit hyperactivity
disorder: implications for management.
 
Pliszka SR.
 
Division of Child and Adolescent Psychiatry, Department of Psychiatry, The
University of Texas Health Science Center at San Antonio, San Antonio, Texas,
USA.
 
Attention deficit hyperactivity disorder (ADHD) is frequently comorbid with a
variety of psychiatric disorders. These include oppositional defiant disorder
and conduct disorder (CD), as well as affective, anxiety, and tic disorders.
ADHD and ADHD with comorbid CD appear to be distinct subtypes; children with
ADHD/CD are at higher risk of antisocial personality and substance abuse as
adults. Stimulants are often effective treatments for aggressive or antisocial
behavior in patients with ADHD, but mood stabilizers or atypical antipsychotics
may be used to treat explosive aggressive outbursts. Response to stimulants is
not affected by comorbid anxiety, but children with ADHD/anxiety disorder may
show greater benefit from psychosocial interventions than those with ADHD alone.
The degree of prevalence of major depressive disorder (MDD) and bipolar disorder
among children with ADHD is controversial, but a subgroup of severely
emotionally labile ADHD children who present serious management issues for the
clinician clearly exists. Antidepressants may be used in conjunction with
stimulants to treat MDD, while mood stabilizers and atypical antipsychotics are
often required to treat manic symptoms or aggression. After resolution of the
manic episode, stimulant treatment of the comorbid ADHD may be safely
undertaken. Recent research suggests that stimulants can be safely used in
children with comorbid ADHD and tic disorders, but the addition of anti-tic
agents to stimulants is often necessary. Clinicians who work with patients with
ADHD should be prepared to deal with a wide range of emotional and behavioral
problems beyond the core symptoms of inattention and impulsivity/hyperactivity.
 
PMID: 14580223 [PubMed - in process]
<HR>
7: Curr Opin Pediatr. 2003 Oct;15(5):476-82. 
 
Assessment and treatment of attention deficit hyperactivity disorder in children
with comorbid psychiatric illness.
 
Waxmonsky J.
 
State University of New York at Buffalo, Department of Psychiatry, USA.
jgw@buffalo.edu
 
PURPOSE OF REVIEW: Attention deficit hyperactivity disorder (ADHD) frequently
occurs with a wide variety of comorbid psychiatric disorders such as conduct
disorder, depression, mania, anxiety, and learning disabilities. Because the
vast majority of children with ADHD are treated in primary care settings, it is
important that primary medical doctors be proficient in the diagnosis and
initial treatment of children with ADHD and its commonly occurring comorbid
disorders. ADHD research is beginning to focus on the treatment of these
comorbidly ill children. This review will summarize the recent findings from the
psychiatric literature in an attempt to provide the clinician with some initial
diagnostic and treatment guidelines for ADHD and its comorbidities. RECENT
FINDINGS: The NIMH Multimodal Treatment Study of ADHD found that children with
other disruptive behavior disorders plus ADHD respond well to stimulant
medications, with behavioral interventions reducing academic and social
impairment. Children with anxiety and ADHD are very responsive across multiple
dimensions to behavioral and pharmacological ADHD treatments. Much less is known
about the impact of depression on ADHD, and significant debate exists
surrounding the identification and treatment of bipolar disorder in children
with ADHD. Children with learning disabilities respond well to stimulants but
often require additional educational supports. New findings suggest that
treating ADHD may prevent the development of future psychiatric disorders.
SUMMARY: The presence of comorbid illness is associated with significant
additional morbidity and complicates the diagnosis, treatment, and prognosis of
ADHD. Therefore, it is important to identify and treat any comorbid psychiatric
conditions in a child with ADHD.
 
Publication Types:
 Review
 Review, Tutorial
 
PMID: 14508296 [PubMed - indexed for MEDLINE]
<HR>
Int J Neuropsychopharmacol. 2003 Jun;6(2):139-44. 
 
Bipolar comorbidity: from diagnostic dilemmas to therapeutic challenge.
 
Sasson Y, Chopra M, Harrari E, Amitai K, Zohar J.
 
Chaim Sheba Medical Centre, Division of Psychiatry, Tel Hashomer, Israel.
 
Comorbidity in bipolar disorder is the rule rather than the exception more than
60% of bipolar patients have a comorbid diagnosis and is associated with a mixed
affective or dysphoric state; high rates of suicidality; less favourable
response to lithium and poorer overall outcome. There is convincing evidence
that rates of substance use and anxiety disorders are higher among patients with
bipolar disorder compared to their rates in the general population. The
interaction between anxiety disorders and substance use goes both ways: patients
with bipolar disorder have a higher rate of substance use and anxiety disorder,
and vice versa. Bipolar disorder is also associated with borderline personality
disorder and ADHD, and to a lesser extent with weight gain. As more than 40% of
bipolar patients have anxiety disorder, it is indicated that while diagnosing
bipolar patients, systematic enquiry about different anxiety disorders is called
for. This also presents a therapeutic challenge, since agents that effectively
treat anxiety disorders are associated with the risk of induced mania.
Therefore, the treating psychiatrist needs to carefully evaluate the potential
benefit of treating the anxiety against the potential cost of inducing a manic
episode. A possible solution would be to use, when possible, a
non-pharmacological intervention, such as a cognitivebehavioural approach.
Alternately, it is suggested that the clinician attempts to ensure that the
patient receives adequate treatment with mood stabilizers before slowly and
carefully attempting the addition of anti-anxiety compounds with a relatively
lower risk of mania induction (e.g. SSRIs compared to TCAs).
 
PMID: 12890307 [PubMed - indexed for MEDLINE]
<HR>
J Child Adolesc Psychopharmacol. 2003 Summer;13(2):123-36. 
 
Response to methylphenidate in children with attention deficit hyperactivity
disorder and manic symptoms in the multimodal treatment study of children with
attention deficit hyperactivity disorder titration trial.
 
Galanter CA, Carlson GA, Jensen PS, Greenhill LL, Davies M, Li W, Chuang SZ,
Elliott GR, Arnold LE, March JS, Hechtman L, Pelham WE, Swanson JM.
 
Columbia University/New York State Psychiatric Institute, New York, New York
10032, USA. cg168@columbia.edu
 
OBJECTIVE: Recent reports raise concern that children with attention deficit
hyperactivity disorder (ADHD) and some manic symptoms may worsen with stimulant
treatment. This study examines the response to methylphenidate in such children.
METHODS: Data from children participating in the 1-month methylphenidate
titration trial of the Multimodal Treatment Study of Children with ADHD were
reanalyzed by dividing the sample into children with and without some manic
symptoms. Two "mania proxies" were constructed using items from the Diagnostic
Interview Schedule for Children (DISC) or the Child Behavior Checklist (CBCL).
Treatment response and side effects are compared between participants with and
without proxies. RESULTS: Thirty-two (11%) and 29 (10%) participants fulfilled
criteria for the CBCL mania proxy and DISC mania proxy, respectively. Presence
or absence of either proxy did not predict a greater or lesser response or side
effects. CONCLUSION: Findings suggest that children with ADHD and manic symptoms
respond robustly to methylphenidate during the first month of treatment and that
these children are not more likely to have an adverse response to
methylphenidate. Further research is needed to explore how such children will
respond during long-term treatment. Clinicians should not a priori avoid
stimulants in children with ADHD and some manic symptoms.
 
PMID: 12880507 [PubMed - indexed for MEDLINE]
<HR>
Biol Psychiatry. 2003 Jul 1;54(1):9-16. 
 
An open trial of bupropion for the treatment of adults with
attention-deficit/hyperactivity disorder and bipolar disorder.
 
Wilens TE, Prince JB, Spencer T, Van Patten SL, Doyle R, Girard K, Hammerness P,
Goldman S, Brown S, Biederman J.
 
Clinical Research Program in Pediatric Psychopharmacology, Massachusetts General
Hospital, Harvard Medical School, Boston, Massachusetts, USA.
 
BACKGROUND: Despite the increasing recognition of comorbid
attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BPD) in
adults, there are no prospective trials of pharmacological agents to treat ADHD
in these patients. Given the efficacy of bupropion for ADHD in adults, as well
as its use in the management of bipolar depression, we studied the tolerability
and efficacy of sustained-release (SR) bupropion in adults with ADHD plus BPD.
METHODS: This was an open, prospective, 6-week trial of bupropion SR (up to 200
mg b.i.d.) in adults with DSM-IV ADHD plus historical bipolar I disorder (BPD I)
(10%) or bipolar II disorder (BPD II) (90%). Adults receiving adjunct antimanic
agents (mood stabilizers and antipsychotics) at baseline were included in the
study. We used standardized psychiatric instruments for diagnosis and outcome.
Efficacy was based primarily on the Clinical Global Impression Scale (CGI) for
ADHD and the ADHD symptom checklist. RESULTS: Of 36 patients entered (75% male,
mean age 34 years), 30 patients (83%) completed the protocol. At end point (last
observation carried forward [LOCF]) compared to baseline, treatment with
bupropion SR resulted in significant reductions in the ADHD symptom checklist
(-55%, z = 5.63, p <.001) and CGI severity of ADHD (-40%, z = 6.285, p <.001).
Bupropion was associated with reductions in ratings of mania and depression.
CONCLUSIONS: The results from this open study of adults with ADHD plus BPD
suggest that sustained-release bupropion may be effective in treating ADHD in
the context of a lifetime diagnosis of BPD, without significant activation of
mania. Further controlled trials are warranted.
 
Publication Types:
 Clinical Trial
 
PMID: 12842303 [PubMed - indexed for MEDLINE]
<HR>
Biol Psychiatry. 2003 Jul 1;54(1):1-8. 
 
Can adults with attention-deficit/hyperactivity disorder be distinguished from
those with comorbid bipolar disorder? Findings from a sample of clinically
referred adults.
 
Wilens TE, Biederman J, Wozniak J, Gunawardene S, Wong J, Monuteaux M.
 
Clinical Research Program in Pediatric Psychopharmacology, Massachusetts General
Hospital, Harvard Medical School, Boston, Massachusetts, USA.
 
BACKGROUND: Despite data describing the overlap of attention deficit
hyperactivity disorder (ADHD) and bipolar disorder (BPD) in youth, little is
known about adults with these co-occurring disorders. We now evaluate the
clinical characteristics of referred adults with (n = 24) and without BPD (n =
27). METHODS: Referred adults to clinical trials of ADHD were evaluated by
psychiatric evaluation using DSM-IV criteria. Structured psychiatric interviews
were used to systematically assess adult and childhood disorders. RESULTS: The
vast majority of patients with ADHD plus BPD had bipolar II disorder (88%).
Adults with ADHD plus BPD had higher rates of the combined subtype of ADHD
compared to ADHD without BPD (chi(2) = 8.7, p =.003), a greater number of DSM-IV
ADHD symptoms (14.8 +/- 2.9 and 11.4 +/- 4.0; t = -3.4, p <.01), more
attentional symptoms of ADHD (8.1 +/- 1.4 and 6.8 +/- 2.1; t = -2.5, p <.02;
trend), poorer global functioning (47 +/- 5.9 and 52 +/- 7.4, t = 2.6, p <.02;
trend), and additional comorbid psychiatric disorders (3.7 +/- 2.5 and 2.0 +/-
1.9; t = -2.9, p <.01). CONCLUSIONS: These results suggest that adults with ADHD
plus BPD have prototypic symptoms of both disorders, suggesting that both
disorders are present and are distinguishable clinically.
 
PMID: 12842302 [PubMed - indexed for MEDLINE]
<HR>
J Child Psychol Psychiatry. 2003 May;44(4):612-36. 
 
The validity of analyses testing the etiology of comorbidity between two
disorders: a review of family studies.
 
Rhee SH, Hewitt JK, Corley RP, Stallings MC.
 
Institute for Behavioral Genetics, University of Colorado, Boulder 80309, USA.
soo.rhee@colorado.edu
 
BACKGROUND: Knowledge regarding the causes of comorbidity between two disorders
has a significant impact on research regarding the classification, treatment,
and etiology of the disorders. Two main analytic methods have been used to test
alternative explanations for the causes of comorbidity in family studies:
biometric model fitting and family prevalence analyses. Unfortunately, the
conclusions of family studies using these two methods have been conflicting. In
the present study, we examined the validity of family prevalence analyses in
testing alternative comorbidity models. METHOD: We reviewed 42 family studies
that used family prevalence analyses to test three comorbidity models: the
alternate forms model, the correlated liabilities model, or the three
independent disorders model. We conducted the analyses used in these studies on
datasets simulated under the assumptions of 13 alternative comorbidity models
including the three models tested most often in the literature. RESULTS: Results
suggest that some analyses may be valid tests of the alternate forms model
(i.e., two disorders are alternate manifestations of a single liability), but
that none of the analyses are valid tests of the correlated liabilities model
(i.e., a significant correlation between the risk factors for the two disorders)
or the three independent disorders model (i.e., the comorbid disorder is a
third, independent disorder). CONCLUSION: Family studies using family prevalence
analyses may have made incorrect conclusions regarding the etiology of
comorbidity between disorders.
 
Publication Types:
 Review
 Review, Academic
 Validation Studies
 
PMID: 12751852 [PubMed - indexed for MEDLINE]
<HR>
J Am Acad Child Adolesc Psychiatry. 2003 May;42(5):552-60. 
 
Manic symptoms in young males with ADHD predict functioning but not diagnosis
after 6 years.
 
Hazell PL, Carr V, Lewin TJ, Sly K.
 
Center for Mental Health Studies, University of Newcastle, Newcastle, New South
Wales, Australia. hazell@mail.newcastle.edu.au
 
OBJECTIVE: To compare the outcome in early adulthood of males who met criteria
for attention-deficit/hyperactivity disorder (ADHD) and mania, ADHD alone, or no
psychiatric disorder when aged 9-13 years. METHOD: Males who met criteria at
baseline assessment conducted in the period 1992-1994 for mania+ADHD (n = 15),
ADHD without mania (n = 65), or no psychiatric diagnosis (n = 17) were
reevaluated after 6 years using computer-assisted structured interviews for Axis
I and Axis II disorders, questionnaires about functioning and service
utilization, and a clinician-rated assessment of global functioning. RESULTS:
There were no group differences in the prevalence of Axis I or Axis II
disorders, with the exception of alcohol abuse, which was higher in controls.
Manic symptoms persisted in only one mania+ADHD subject, while three (5%) of the
ADHD subjects had new-onset manic symptoms. There were no clear cases of bipolar
disorder. The groups were not distinguished on levels of service utilization or
criminal behavior, but global functioning was significantly lower at follow-up
in the mania+ADHD group compared with controls. CONCLUSIONS: Although a pilot
study in scope, the findings cast doubt on a link between mania symptoms
associated with ADHD in childhood and later bipolar disorder.
 
PMID: 12707559 [PubMed - indexed for MEDLINE]
<HR>
Am J Psychiatry. 2002 Jun;159(6):927-33. 
 
Comment in:
 Am J Psychiatry. 2002 Jun;159(6):893-4.
 
Two-year prospective follow-up of children with a prepubertal and early
adolescent bipolar disorder phenotype.
 
Geller B, Craney JL, Bolhofner K, Nickelsburg MJ, Williams M, Zimerman B.
 
Department of Psychiatry, Washington University School of Medicine, St. Louis,
MO 63110, USA. gellerb@medicine.wustl.edu
 
OBJECTIVE: Longitudinal outcomes of bipolar disorder with onset in the late
teenage years or in adulthood have been reported, but little is known about the
natural history of childhood-onset mania. This study sought to provide rates and
predictors of recovery and relapse in children with a prepubertal and early
adolescent bipolar disorder phenotype. METHOD: Eighty-nine consecutively
ascertained outpatient subjects (mean age=10.9 years [SD=2.7]) received
comprehensive research assessments, including separate interviews of mothers
about their children and of children about themselves, at baseline and at 6, 12,
18, and 24 months after baseline. The study phenotype required DSM-IV mania with
elation and/or grandiosity as one criterion to distinguish the study phenotype
from a diagnosis of mania based on criteria overlapping with those for attention
deficit hyperactivity disorder and to ensure that subjects had at least one of
the two cardinal features of mania (i.e., elation and/or grandiosity). Subjects
were treated by their own community practitioners. RESULTS: The proportions of
subjects who recovered from mania and who relapsed after recovery were 65.2% and
55.2%, respectively. The mean time to recovery was 36.0 weeks (SD=25.0). Relapse
occurred after a mean of 28.6 weeks (SD=13.2). Living with an intact biological
family significantly predicted rate of recovery, and a low level of maternal
warmth significantly predicted rate of relapse. CONCLUSIONS: The relatively poor
outcomes of these subjects may be related to their phenotypic resemblance to
severely ill adults with bipolar disorder who have mixed mania, continuous rapid
cycling, psychosis, and treatment-resistant psychopathology. A lower level of
effectiveness of mood stabilizers in children cannot be ruled out. Although the
significance of maternal warmth as a predictor is consistent with reports in
adult mania, the significance of intact family as a predictor may be unique to
childhood mania.
 
PMID: 12042179 [PubMed - indexed for MEDLINE]
>HR>
J Child Adolesc Psychopharmacol. 2002 Spring;12(1):63-7. 
 
Can stimulant rebound mimic pediatric bipolar disorder?
 
Sarampote CS, Efron LA, Robb AS, Pearl PL, Stein MA.
 
Department of Psychology, Children's National Medical Center, George Washington
University School of Medicine, Washington, DC 20010, USA.
 
The authors describe the case of a 7-year-old girl diagnosed with attention
deficit hyperactivity disorder (ADHD) who, following an unsuccessful trial of
stimulant medication and subsequent mood symptoms, was diagnosed with bipolar
disorder. Following a comprehensive, multidisciplinary assessment, and
withdrawal of her complex medication regimen, she was rediagnosed with ADHD. She
displayed a positive response to behavioral parent training and pharmacological
treatment with a long-acting stimulant. The case illustrates the benefits of a
comprehensive, multidisciplinary evaluation and multimodal treatment. Her
dramatic response to the long-acting stimulant suggests that many of her
affective symptoms were due to stimulant "rebound" versus bipolar disorder. This
case highlights the complexities of differentiating severe ADHD from bipolar
disorder and suggests that stimulant rebound and other iatrogenic effects should
be considered during the differential diagnostic process as potential mimics of
bipolar disorder.
 
Publication Types:
 Case Reports
 
PMID: 12014597 [PubMed - indexed for MEDLINE]
<HR>
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. gellerb@medicine.wustl.edu
 
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
mania.
 
Publication Types:
 Clinical Trial
 Controlled Clinical Trial
 
PMID: 12014591 [PubMed - indexed for MEDLINE]
<HR>
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,
USA. doylea@helix.mgh.harvard.edu
 
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.
 
Publication Types:
 Review
 Review, Tutorial
 
PMID: 11914177 [PubMed - indexed for MEDLINE]
<HR>
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]
<HR>
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.
 
Publication Types:
 Case Reports
 
PMID: 11642481 [PubMed - indexed for MEDLINE]
<HR>
J Neuropsychiatry Clin Neurosci. 2001 Summer;13(3):385-95. 
 
Impairments of attention and effort among patients with major affective
disorders.
 
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. rac@brown.edu
 
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]
<HR>
J Clin Psychiatry. 2001;62 Suppl 14:10-5. 
 
Diagnostic and therapeutic dilemmas in the management of pediatric-onset bipolar
disorder.
 
Wozniak J, Biederman J, Richards JA.
 
Pediatric Psychopharmacology Unit of the Child Psychiatry Service, Massachusetts
General Hospital, Harvard Medical School, Boston 02114, USA.
wozniak@helix.mgh.harvard.edu
 
Although the diagnosis of pediatric-onset bipolar disorder is controversial, an
increasing literature of systematic research has challenged the traditional view
that this disorder is a rare condition. This article summarizes research
regarding the atypical presentation of pediatric bipolar disorder and its
overlap with attention-deficit/hyperactivity disorder and other comorbid
conditions, as well as family-genetic and treatment data. When structured
interview data were examined, cases of pediatric mania constituted 16% of
referrals to our outpatient clinic. Presentation is atypical by adult standards
and includes irritability, chronicity, and mixed state. Family-genetic and
treatment data help to establish diagnostic validity. Pediatric bipolar disorder
is not a rare condition. Treatment requires a combined pharmacotherapy approach
to address issues of comorbidity. Atypical antipsychotic medications have
provided promising treatment results, but additional controlled clinical trials
are needed.
 
Publication Types:
 Review
 Review, Tutorial
 
PMID: 11469669 [PubMed - indexed for MEDLINE]
<HR>
J Affect Disord. 2001 Jul;65(2):197-215. 
 
Evolutionary recasting: ADHD, mania and its variants.
 
Brody JF.
 
jbrody@compuserve.com
 
This paper reviews clinical observations and evolutionary theory in relation to
attention deficit hyperactivity disorder (ADHD) on the one hand and mania and
its variants on the other. Both groups of disorders resemble each other in
regard to high levels of motor activity, perhaps occurring together more often
than not, and are confounded in most existing research. Making distinctions
requires isolating the contribution of activity level from other characteristics
such as those of flawed executive functions for ADHD or grandiosity and lapses
in reciprocity for mania. High activity level is an asset throughout nature
except in extreme intensities or when it amplifies the characteristics of
psychopathology. Fitness, social displays, and behavioral adaptations for
survival are clues to some aspects of hypomania and ADHD. While hypomania can be
a competitive advantage in certain niches, it appears there can be few
opportunities for ADHD to do so. Indeed, the impulsiveness seen in ADHD is
probably the outcome of flaws in executive functions rather than being the cause
of them. Neither lapses in executive functions nor in reciprocity are apt to be
domain general but may interact sharply with each person's repertoire of
psychological adaptations. The author submits that a theoretical orientation as
outlined here would not only help in better understanding the disorders under
consideration, but could be useful in providing new directions to treatment
decisions.
 
Publication Types:
 Review
 Review, Tutorial
 
PMID: 11356245 [PubMed - indexed for MEDLINE]
<HR>
Bipolar Disord. 2001 Apr;3(2):58-62. 
 
Persistent attentional dysfunction in remitted bipolar disorder.
 
Wilder-Willis KE, Sax KW, Rosenberg HL, Fleck DE, Shear PK, Strakowski SM.
 
Bipolar and Psychotic Disorders Research Program, Department of Psychiatry,
University of Cincinnati College of Medicine, OH 45267-0559, USA.
 
OBJECTIVES: Although previous research has shown that attentional dysfunction is
common during acute mood episodes in individuals with bipolar disorder (BPD),
few studies have examined whether attentional deficits are evident during
periods of symptom stability. The goal of this study was to determine whether
clinically stable individuals with BPD would have attentional disturbances
relative to healthy subjects. METHODS: Fourteen patients with BPD and 12 healthy
comparison subjects participated in the study, and were administered the
Degraded Stimulus Continuous Performance Test (DSCPT), Digit Span
Distractibility Test (DSDT) and Grooved Pegboard Test (GPT). Psychiatric
symptoms were assessed with the Young Mania Rating Scale and the Scale for the
Assessment of Positive Symptoms. Medication side effects were measured with the
Simpson Rating Scale. RESULTS: The patient group responded significantly more
slowly than the control group on the DSCPT (z = -2.52, p = 0.01) and the GPT (z
= -3.37, p = 0.001). There was a trend towards the BPD patients demonstrating
impaired perceptual sensitivity on the DSCPT (z = 1.68, p = 0.09). The two
groups did not differ on the DSDT (z = -1.06, p = 0.3). Poor performance on the
GPT and DSCPT target reaction time were not associated with symptom ratings or
medications. CONCLUSION: The findings suggest that impairments in fine motor
skills and reaction time may be present in clinically stable patients with BPD,
even after accounting for psychiatric symptoms and medication effects.
Performance decrements on attentional tasks may be in part reflective of motor
impairments in patients with BPD.
 
PMID: 11333063 [PubMed - indexed for MEDLINE]
<HR>
J Affect Disord. 2001 Apr;64(1):19-26. 
 
Attention deficit hyperactivity disorder with bipolar disorder in girls: further
evidence for a familial subtype?
 
Faraone SV, Biederman J, Monuteaux MC.
 
Pediatric Psychopharmacology Unit, Psychiatry Service, ACC 725, Massachusetts
General Hospital, Fruit Street, Boston, MA 02114, USA. faraone@mediaone.net
 
BACKGROUND: To clarify the nosologic status of girls with attention deficit
hyperactivity disorder (ADHD) who also satisfy diagnostic criteria for bipolar
disorder (BPD). METHODS: Using blind raters and structured psychiatric
interviews, we examined 140 girls with ADHD, 122 non-ADHD comparisons and their
786 first degree relatives. Analyses tested specific hypotheses about the
familial relationship between ADHD and bipolar disorder in girls. RESULTS: After
stratifying our ADHD sample into those with and without BPD, we found that: (1)
relatives of both ADHD subgroups were at significantly greater risk for ADHD
than relatives of non-ADHD controls, (2) the two subgroups did not significantly
differ in their relatives' risk for ADHD; (3) an elevated risk for bipolar
disorder was observed among relatives when the proband child had BPD but not
ADHD alone; (4) weak evidence of cosegregation between ADHD and BPD, and (5) no
evidence of a trend for random mating between ADHD parents and those with mania.
LIMITATIONS: Limitations of this study include the lack of direct interviewing
of probands and the limited number of ADHD/BPD probands available. CONCLUSIONS:
These findings extend to girls what was previously documented in boys and
suggest that comorbid ADHD with BPD in girls is familially distinct from other
forms of ADHD and may be related to what others have termed childhood onset BPD.
Future work could determine if this subgroup has a characteristic course,
outcome and response to treatment.
 
PMID: 11292516 [PubMed - indexed for MEDLINE]
<HR>
J Am Acad Child Adolesc Psychiatry 2000 Dec;39(12):1543-8

Psychosocial functioning in a prepubertal and early adolescent bipolar disorder phenotype.

Geller B, Bolhofner K, Craney JL, Williams M, DelBello MP, Gundersen K

Department of Psychiatry, Washington University School of Medicine, St. Louis 63110, USA. gellerb@medicine.wustl.edu

OBJECTIVE: To compare psychosocial functioning (PF) in a prepubertal and early adolescent bipolar disorder phenotype (PEA-BP) sample to two comparison groups, i.e., attention-deficit/hyperactivity disorder (ADHD) and community controls (CC). METHOD: There were 93 PEA-BP (with or without comorbid ADHD), 81 ADHD, and 94 CC subjects who were participants in an ongoing study, the Phenomenology and Course of Pediatric Bipolar Disorders. Cases in the PEA-BP and ADHD groups were outpatients obtained by consecutive new case ascertainment, and CC subjects were from a survey conducted by the Research Triangle Institute. To fit the study phenotype, PEA-BP subjects needed to have current DSM-IV mania or hypomania with elation and/or grandiosity as one criterion. Assessments for PF were by experienced research nurses who were blind to group status. Mothers and children were separately interviewed with the Psychosocial Schedule for School Age Children-Revised. RESULTS: Compared with both ADHD and CC subjects, PEA-BP cases had significantly greater impairment on items that assessed maternal-child warmth, maternal-child and paternal-child tension, and peer relationships. CONCLUSIONS: Clinicians need to consider PF deficits when planning interventions. In the PEA-BP group, there was a 43% rate of hypersexuality with a 

<1% rate of sexual abuse, supporting hypersexuality as a manifestation of child mania.>

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J Child Adolesc Psychopharmacol 2000 Fall;10(3):175-84
Stimulant treatment in young boys with symptoms suggesting childhood mania: a report from a longitudinal study. Carlson GA, Loney J, Salisbury H, Kramer JR, Arthur C
Division of Child and Adolescent Psychiatry, State University of New York at Stony Brook, 11794-8790, USA. Gcarlson@mail.psychiatry.sunysb.edu
This study used data from a completed longitudinal study to examine the effects of methylphenidate on 6-12-year-old boys presumably at risk for bipolar disorder. Of 75 boys referred, diagnosed with hyperkinetic reaction of childhood (minimal brain dysfunction), treated clinically with methylphenidate, and followed as young adults, 23% (the maximorbid or MAX group) had childhood symptoms of irritability and emulated DSM-IV diagnoses of attention deficit hyperactivity disorder (ADHD), plus oppositional defiant or conduct disorder (ODD/CD) and anxiety or depression or both. The remaining boys (the minimorbid or MIN group) had fewer symptoms and disorders. MAX and MIN groups did not differ in rated response to methylphenidate, duration of treatment, clinically determined maintenance doses, concurrent or subsequent treatment with other medications, or other aspects of medication experience. At ages 21-23, individuals with bipolar-related lifetime diagnoses (adult mania, hypomania, or cyclothymia) did not differ from those without bipolar-related diagnoses in any aspect of early methylphenidate treatment history. These findings indicate that ADHD boys with symptoms suggesting childhood mania do not respond differently to methylphenidate than boys without such symptoms, and there is no evidence here that methylphenidate precipitates young adult bipolar disorders in susceptible individuals.

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J Child Adolesc Psychopharmacol 2000 Fall;10(3):157-64
Diagnostic characteristics of 93 cases of a prepubertal and early adolescent bipolar disorder phenotype by gender, puberty and comorbid attention deficit hyperactivity disorder.
Geller B, Zimerman B, Williams M, Bolhofner K, Craney JL, Delbello MP, Soutullo CA
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, USA. gellerb@medicine.wustl.edu
OBJECTIVE: Etiopathogenetic and treatment studies require homogeneous phenotypes. Therefore, effects of gender, puberty, and comorbid attention deficit hyperactivity disorder (ADHD) on DSM-IV mania criteria and other characteristics of a prepubertal and early adolescent bipolar disorder (PEA-BP) phenotype were investigated. METHOD: Consecutively ascertained PEA-BP (with or without comorbid ADHD) outpatients (n = 93) were blindly assessed by research nurses with comprehensive instruments given to mothers and children separately, consensus conferences, and offsite blind best estimates of both diagnoses and mania items. To fit the study phenotype, subjects needed to have current DSM-IV mania or hypomania with elated mood and/or grandiosity as one criterion and to be definite cases by severity ratings. RESULTS: Subjects were aged 10.9 +/- 2.6 years, had current episode length of 3.6 +/- 2.5 years, and had early age of onset at 7.3 +/- 3.5 years. No significant differences were found by gender, puberty, or comorbid ADHD on rates of mania criteria (e.g., elation, grandiosity, racing thoughts), mixed mania, psychosis, rapid cycling, suicidality, or comorbid oppositional defiant disorder (ODD), with few exceptions. Subjects with comorbid ADHD were more likely to be younger and male. Pubertal subjects had higher rates of hypersexuality. CONCLUSIONS: These findings support that the PEA-BP phenotype is homogeneous except for differences (hyperactivity, hypersexuality) that mirror normal development.

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Am J Addict 2000 Summer;9(3):187-95
Is bipolar disorder a risk for cigarette smoking in ADHD youth?
Wilens TE, Biederman J, Milberger S, Hahesy AL, Goldman S, Wozniak J, Spencer TJ
Pediatric Psychopharmacology Unit, Massachusetts General Hospital, Boston 02114, USA. wilens@helix.mgh.harvard.edu
Despite emerging literature linking juvenile bipolar disorder (BPD) and substance abuse, little is known about a link between BPD and cigarette smoking. To this end, we evaluated the association between BPD and cigarette smoking in youth. Subjects were 31 bipolar adolescents derived from a cohort of boys with DSM-III-R ADHD (N = 128) and non-ADHD comparisons (N = 109) followed prospectively for 4 years into mid-adolescence. Information on cigarette smoking was obtained in a standardized manner blind to the proband's clinical status. Logistic regression models were used to determine risk for smoking at follow-up. BPD was associated with a higher risk for cigarette smoking in mid-adolescence, which was largely accounted for by conduct disorder. The developmental onset of BPD in adolescence (age 13-18 years) conferred a greater risk for cigarette smoking compared to those youths with the onset of their BPD prepubertally (< or = 12 years; odds ratio = 10.8, p < 0.01), even after controlling for conduct disorder and other confounds. The naturalistic treatment of BPD with combined counseling and pharmacotherapy appeared to reduce the risk for cigarette smoking. BPD, particularly when it onsets in adolescence, is a significant risk factor for the early initiation of cigarette smoking in these ADHD youths. These data coupled with the literature strongly suggest that juveniles with BPD need to be carefully monitored for the early initiation of cigarette smoking and substance abuse.

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Child Adolesc Psychiatr Clin N Am 2000 Jul;9(3):525-40
Patterns of psychiatric comorbidity with attention-deficit/hyperactivity disorder.
Pliszka SR
Department of Psychiatry, University of Texas Health Science Center at San Antonio, USA. pliszka@uthscsa.edu
Attention deficit/hyperactivity disorder (ADHD) is frequently comorbid with a variety of psychiatric disorders. These disorders include oppositional defiant (ODD) and conduct disorders (CD), and affective, anxiety, and learning disorders. Studies which have examined the comorbidity of these disorders with ADHD are reviewed. ADHD and ADHD with CD seem to be distinct subtypes; children with ADHD/CD are at higher risk of antisocial personality as adults. Coexisting anxiety may attenuate impulsivity in ADHD. Studies examining stimulant response in children with ADHD/anxiety have recently yielded conflicting results. Anxiety and ADHD seem to be inherited independently. The prevalence of major depressive disorder (MDD) and bipolar disorder among children with ADHD is controversial, but there clearly exists a subgroup of severely emotionally labile children with ADHD who present serious management issues for the clinician. About 20% to 25% of children with ADHD meet criteria for a learning disorder (LD), but LD seems to be independent of ADHD.

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J Clin Psychiatry 2000;61 Suppl 9:31-4
Bipolar disorder and attention-deficit/hyperactivity disorder in children and adolescents.
Giedd JN
Child Psychiatry Branch, National Institute of Mental Health, Bethesda, Md 20892, USA. jgiedd@helix.nih.gov
The relationship between bipolar disorder and attention-deficit/hyperactivity disorder (ADHD) in children and adolescents has been one of the most hotly debated topics in recent child psychiatry literature. At the heart of the matter is whether large numbers of children with bipolar disorder are being unrecognized or misdiagnosed. The differential diagnoses of juvenile-onset bipolar disorder can be complicated by many factors, but the most common clinical dilemmas seem to arise from overlapping symptomatology with ADHD and the differing treatment strategies these diagnoses imply. This article discusses the similarities and differences between these disorders with respect to phenomenology, epidemiology, family history, brain imaging, and treatment response.

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J Affect Disord 1998 Nov;51(2):177-87
Mania and ADHD: comorbidity or confusion.
Carlson GA
Department of Psychiatry and Behavioral Sciences, Child and Adolescent Psychiatry, State University of New York at Stony Brook, 11794-8790, USA. GCarlson@mail.psychiatry.sunysb.edu
The frequency of occurrence of prepubertal mania is contingent on how much adherence to episodic disorder with separate periods of mania and depression is required. While manic symptoms superimposed on other psychiatric disorders is not uncommon, non-comorbid bipolar disorder is rare. A number of developmental, phenomenological and assessment considerations may complicate simple extrapolation of adult criteria onto young children. Nevertheless, it is clear that a significant number of preadolescents found in outpatient and inpatient samples meet at least symptom criteria for bipolar disorder. Such children have significant comorbidity and impairment. It is likely that some may develop classical bipolar disorder, some will continue to have substantial affective and behavioral comorbidity as do some complicated bipolar adults, and some will continue to have affective lability superimposed on their other, primary psychiatric disorders. Further research and follow-up will be necessary to determine who develops which outcome.

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J Affect Disord 1998 Nov;51(2):145-51
Early childhood attention deficit hyperactivity disorder predicts poorer response to acute lithium therapy in adolescent mania.
Strober M, DeAntonio M, Schmidt-Lackner S, Freeman R, Lampert C, Diamond J
Neuropsychiatric Institute and Hospital, School of Medicine, University of California at Los Angeles, 90024-1759, USA. mstrober@mednet.ucla.edu
We compared the response to acute lithium therapy in 30 adolescents, 13-17 years of age, with mania and a prior history of early childhood attention deficit hyperactivity disorder (ADHD) to a sex- and age-matched control group of adolescent manics without premorbid psychiatric illness. Response to treatment was assessed daily over the course of 28 days using measures of global clinical improvement and severity ratings on the Bech-Rafaelsen Mania Scale (BRMS). BRMS scores decreased by a mean of 24.3 in the subgroup without prior ADHD compared to 16.7 in patients with ADHD (P = 0.0005). The average percent drop in BRMS scores over the study period in these two subgroups was 80.6% and 57.7%, respectively (P = 0.0005). Time to onset of sustained global clinical improvement was also assessed using Kaplan-Meier survival methods and possible covariates of time to improvement were tested in a Cox proportional hazards model. Median time to onset of sustained improvement was lengthened significantly in patients with early ADHD (23 days) compared to those without it (17 days; log rank chi2 = 7.2, P = 0.007). The results suggest that early childhood ADHD defines an important source of heterogeneity in bipolar illness with developmental, clinical, and neuropharmacogenetic implications.

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J Affect Disord 1998 Nov;51(2):101-12
Clinical features of children with both ADHD and mania: does ascertainment source make a difference?
Biederman J, Russell R, Soriano J, Wozniak J, Faraone SV
Pediatric Psychopharmacology Unit of the Child Psychiatry Service, Massachusetts General Hospital, Boston 02114, USA.
OBJECTIVE: We evaluated the structural diagnostic results of children ascertained through an ADHD diagnosis with comorbid mania to determine if they have the same phenotype as children ascertained through a mania diagnosis with comorbid ADHD. METHOD: We compared a sample of children participating in a family genetic study of ADHD to a sample of children ascertained through a study of childhood mania. RESULTS: Similar correlates of ADHD and mania were observed in children satisfying criteria for both disorders irrespective of ascertainment source. CONCLUSIONS: Findings suggest that children with mania and ADHD have two disorders, their features not varying with the primary diagnostic focus. LIMITATIONS: The results may have been limited by small sample size. CLINICAL RELEVANCE: Because the coexistence of ADHD and mania seriously complicates the course and treatment of children, understanding the compatibility of these disorders has important clinical implications in the management of this population.

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J Affect Disord 1998 Nov;51(2):93-100
Prepubertal and young adolescent bipolarity versus ADHD: assessment and validity using the WASH-U-KSADS, CBCL and TRF.
Geller B, Warner K, Williams M, Zimerman B
Washington University School of Medicine, St. Louis, MO, 63110, USA. gellerb@medicine.wustl.edu
BACKGROUND: This addendum to 'Prepubertal and early adolescent bipolarity differentiate from ADHD by mania criteria; grandiose delusions; ultra-rapid or ultradian cycling' (in this volume) provides (1) a description of Washington University at St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS) with sample sections (hypersexuality, rapid cycling); (2) a comparison of WASH-U-KSADS to KSADS-P/L and KSADS-1986 and (3) a comparison of WASH-U-KSADS to Child Behavior Checklist (CBCL) and Teachers Report Form (TRF) data. METHODS: Data were from the first 60 bipolar (BP) and first 60 ADHD subjects of 270 consecutively ascertained cases (90 BP, 90 ADHD and 90 community controls) in the NIMH funded 'Phenomenology and Course of Pediatric Bipolarity' study. Comprehensive assessments included the WASH-U-KSADS (administered blindly to mothers and separately to children), CBCL and TRF. RESULTS: As reported elsewhere in this volume, WASH-U-KSADS data significantly differentiated BP and ADHD groups. Significant differences were also found with the parent-rated CBCL and the teacher-rated TRF, thereby providing cross-modality and cross-informant validation of the WASH-U-KSADS. Because of the close agreement with published CBCL data from another investigator, cross-site validation also occurred. LIMITATIONS: Venues for consecutive ascertainment from the lowest socioeconomic status classes were unavailable due to current health care policies. CLINICAL RELEVANCE: CBCL and TRF data separated BP from ADHD groups, largely by non-specific externalizing dimensions (e.g., hyperactivity, aggressivity). Clinically relevant differentiation by categorical mania-specific criteria (e.g., elated mood, grandiosity, racing thoughts) occurred with WASH-U-KSADS data. Both types of data are crucial for genetic and neurobiological studies.

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J Affect Disord 1998 Nov;51(2):81-91
Prepubertal and early adolescent bipolarity differentiate from ADHD by manic symptoms, grandiose delusions, ultra-rapid or ultradian cycling.
Geller B, Williams M, Zimerman B, Frazier J, Beringer L, Warner KL
Washington University School of Medicine, St. Louis, MO, 63110, USA. gellerb@medicine.wustl.edu
BACKGROUND: In contrast to differential diagnosis (ddx) of older adolescent and adult bipolarity (BP), which includes schizophrenia and substance use disorders, the main ddx of prepubertal and early adolescent BP is attention-deficit disorder with hyperactivity (ADHD). To address this ddx issue, and to provide prepubertal mania manifestations, interim baseline data are presented from the National Institute of Mental Health (NIMH)-funded study 'Phenomenology and Course of Pediatric Bipolarity'. METHODS: Data are from the first 60 BP and the first 60 ADHD cases from 270 consecutively ascertained subjects (90 BP, 90 ADHD and 90 community controls). Comprehensive assessments included the Washington University at St. Louis Kiddie and Young Adult-Schedule for Affective Disorders and Schizophrenia--Lifetime and Present Episode Version-DSM-IV (WASH-U-KSADS) blindly administered by nurses to mothers about their offspring and to children/adolescents about themselves. Caseness was established by consensus conferences that included diagnostic and impairment data, teacher and school reports, agency records, videotapes and medical charts. RESULTS: Mean baseline age of BP cases was 11.0+/-2.7 years and the mean age at onset of BP was 8.1+/-3.5 years. Elated mood, grandiosity, hypersexuality, decreased need for sleep, racing thoughts and all other mania items except hyperenergetic and distractibility were significantly and substantially more frequent among BP than ADHD cases (e.g., elation: 86.7% BP vs. 5.0% ADHD; grandiosity: 85.0% BP vs. 6.7% ADHD). In the BP group, 55.0% had grandiose delusions, 26.7% had suicidality with plan/intent and 83.3% were rapid, ultra-rapid or ultradian cyclers. LIMITATIONS: Sites for consecutive case ascertainment from the lowest socioeconomic status classes were unavailable due to current health care policies. CLINICAL RELEVANCE: Prepubertal and early adolescent BP cases differentiate from ADHD by mania-specific criteria and commonly present with ultra-rapid or ultradian cycling.

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Am J Psychiatry 2000 Mar;157(3):466-8
Comorbidity of attention deficit hyperactivity disorder with early- and late-onset bipolar disorder.
Sachs GS, Baldassano CF, Truman CJ, Guille C
Clinical Psychopharmacology Unit, Massachusetts General Hospital, Boston, MA 02114, USA. sachsg@aol.com
OBJECTIVE: The relationship between attention deficit hyperactivity disorder (ADHD) and earlier age at onset of affective illness was examined in probands with a history of bipolar disorder. METHOD: The authors assessed 56 adult bipolar subjects. Those with a history of childhood ADHD (N=8) were age and sex matched with bipolar subjects without a history of childhood ADHD (N=8). RESULTS: The age at onset of the first affective episode was lower for the subjects with bipolar disorder and a history of childhood ADHD (mean=12.1 years, SD=4.6) than for those without a history of childhood ADHD (mean=20. 0 years, SD=11.3). CONCLUSIONS: ADHD in children of bipolar probands might identify children at highest risk for development of bipolar disorder.

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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, Faraone SV
Pediatric Psychopharmacology Unit of the Child Psychiatry Service, Massachusetts General Hospital, Boston, USA. biederman@helix.mgh.harvard.edu
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 symptoms.

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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. hazell@mail.newcastle.edu.au
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.

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J Clin Psychiatry 1998;59 Suppl 7:69-75
Addressing comorbidity in adults with attention-deficit/hyperactivity disorder.
Hornig M
Department of Neurology, College of Medicine, University of California, Irvine 92697-4292, USA.
Psychiatric comorbidity complicates the accurate diagnosis and effective treatment of attention-deficit/hyperactivity disorder (ADHD) in adults. This paper examines the influence of comorbidity on treatment responsiveness in ADHD adults, the neurobiological underpinnings of comorbidity, and the potential of different pharmacologic agents to address comorbid states in ADHD. A categorical schema for neurobiological classification of ADHD subtypes is integrated with literature associating specific neurotransmitters with corresponding neurobehavioral abnormalities. Dopamine, for example, is one of several neurotransmitters implicated in bipolar disorder. Serotonin and norepinephrine are implicated in major depression and anxiety disorders, while self-medication for dopamine dysfunction may relate to substance abuse. Norepinephrine and serotonin have each been linked to aggression and impulsive antisocial behaviors. The effective treatment of ADHD with comorbid psychiatric disorders requires knowledge of the neurochemical underpinnings of each disorder and expertise in the application of appropriate pharmacologic tools. Controlled studies assessing treatment outcomes for both comorbid disorders will assist in the development of improved treatment strategies for adults with complicated ADHD.

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Am J Med Genet 1998 Feb 7;81(1):108-16
Bipolar and antisocial disorders among relatives of ADHD children: parsing familial subtypes of illness.
Faraone SV, Biederman J, Mennin D, Russell R
Massachusetts General Hospital, Department of Psychiatry, Harvard Medical School, Boston 02114, USA.
Attention deficit hyperactivity disorder (ADHD) is a familial disorder that is highly comorbid with conduct disorder and sometimes co-occurs with bipolar disorder. This pattern of comorbidity is also seen among relatives of ADHD probands. A growing literature suggests that ADHD with antisocial comorbidity may be nosologically distinct from other forms of ADHD. A similar pattern has been observed for ADHD and bipolar disorder. Given these results, along with the observed comorbidity between conduct and bipolar disorders, we used data from our study of 140 ADHD and 120 control families to determine if conduct and bipolar disorders in ADHD boys should be considered alternative manifestations of the same familial disorder. The probands and their relatives were examined with DSM-III-R structured diagnostic interviews and were assessed for cognitive, achievement, social, school, and family functioning. Our results provide fairly consistent support for the hypothesis that antisocial- and bipolar-ADHD subtypes are different manifestations of the same familial condition. As predicted by this hypothesis, there was a significant three-way association between variables assessing the family history of each disorder. Moreover, when families were stratified into bipolar, antisocial, and other types, few differences emerged between the bipolar and antisocial families.

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J Affect Disord 1998 Jan;47(1-3):113-22
Depression in attention deficit hyperactivity disorder (ADHD) children: "true" depression or demoralization?
Biederman J, Mick E, Faraone SV
Pediatric Psychopharmacology Unit (ACC 725), Massachusetts General Hospital, Boston 02114, USA.
BACKGROUND: The purpose of this study was to further evaluate the nature of the association between major depression (MD) and attention deficit hyperactivity disorder (ADHD) by examining predictors of persistence of MD attending to issues of familiality, adversity and comorbidity. METHODS: Four years of follow-up of 76 depressed ADHD children were analyzed using multivariate regression to determine predictors of persistent MD. RESULTS: Bipolar disorder and higher indices of interpersonal problems predicted MD persistence. In contrast, school difficulty and ADHD-associated measures of severity were not associated with persistent MD. Remission from ADHD was also not statistically significantly associated with remission from MD. CONCLUSIONS: ADHD and MD had independent and distinct courses, indicating that ADHD-associated MD reflects a depressive disorder and not merely demoralization. LIMITATIONS: This study may have reduced power due to stratification of our group of ADHD boys with persistent and remitting MD.

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J Am Acad Child Adolesc Psychiatry 1997 Oct;36(10):1378-87; discussion 1387-90 Attention-deficit hyperactivity disorder with bipolar disorder: a familial subtype?
Faraone SV, Biederman J, Mennin D, Wozniak J, Spencer T
Pediatric Psychopharmacology Unit, Massachusetts General Hospital, Boston, USA.
OBJECTIVE: To clarify the nosological status of children with attention-deficit hyperactivity disorder (ADHD) who also satisfy diagnostic criteria for bipolar disorder (BPD). METHOD: Blind raters and structured psychiatric interviews were used to examine 140 children with ADHD, a sample of 120 non-ADHD comparisons, and their 822 first-degree relatives. Data analyses tested specific hypotheses about the familial relationship between ADHD and BPD. RESULTS: After stratifying the ADHD sample into those with and without BPD, the authors found that (1) relatives of both ADHD subgroups were at significantly greater risk for ADHD than relatives of non-ADHD controls; (2) the two subgroups did not differ significantly from one another in their relatives' risk for ADHD; (3) a fivefold elevated risk for BPD was observed among relatives when the proband child had BPD but not when the proband had ADHD alone; (4) an elevated risk for major depression with severe impairment was found for relatives of ADHD + BPD probands; (5) both ADHD and BPD occurred in the same relatives more often than expected by chance alone; and (6) there was a trend for random mating between ADHD parents and those with mania. CONCLUSIONS: The data suggest that comorbid ADHD with BPD is familially distinct from other forms of ADHD and may be related to what others have termed childhood-onset BPD.

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J Am Acad Child Adolesc Psychiatry 1997 Aug;36(8):1046-55
Is comorbidity with ADHD a marker for juvenile-onset mania?
Faraone SV, Biederman J, Wozniak J, Mundy E, Mennin D, O'Donnell D
Pediatric Psychopharmacology Unit, Child Psychiatry Service, Massachusetts General Hospital, Boston 02114, USA.
OBJECTIVE: To compare the characteristics and correlates of mania in referred adolescents and to determine whether attention-deficit hyperactivity disorder (ADHD) is a marker of very early onset mania. METHOD: From 637 consecutive admissions, 68 children (< or = 12 years) and 42 adolescents (> 13 years) who satisfied criteria for mania were recruited. These were compared with the 527 nonmanic referrals and 100 normal controls. RESULTS: With the exception of comorbidity with ADHD, there were more similarities than differences between the children and adolescents with mania in course and correlates. There was an inverse relationship between the rates of comorbid ADHD and age of onset of mania: higher in manic children intermediate in adolescents with childhood-onset mania, and lower in adolescents with adolescent-onset mania. CONCLUSIONS: ADHD is more common in childhood-onset compared with adolescent-onset cases of bipolar disorder, suggesting that in some cases, ADHD may signal a very early onset of bipolar disorder. Clinical similarities between the child- and adolescent-onset cases provide evidence for the clinical validity of childhood-onset mania.

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J Affect Disord 1997 Jul;44(2-3):177-88
Conduct disorder with and without mania in a referred sample of ADHD children.
Biederman J, Faraone SV, Hatch M, Mennin D, Taylor A, George P
Pediatric Psychopharmacology Unit, Massachusetts General Hospital, Boston 02114, USA.
OBJECTIVE: To test the hypothesis that dysphoric and non-dysphoric types of CD could be distinguished from one another in their patterns of familiality, adversity, and comorbidity. METHODS: We examined 140 ADHD and 120 normal controls at baseline and 4 years later using assessments from multiple domains. We compared ADHD subgroups with and without conduct (CD) and bipolar (BPD) disorders on psychiatric outcomes at a 4-year follow-up, familial psychopathology and psychosocial functioning. RESULTS: We found that ADHD children with both disorders had higher familial and personal risk for mood disorders than those with CD only, who had a higher personal risk for antisocial personality disorder. Among ADHD probands, having both CD and BPD was associated with poorer functioning and an increased risk for psychiatric hospitalization. DISCUSSION: Although preliminary, our findings suggest that the distinction between dysphoric and non-dysphoric CD may be clinically meaningful. If confirmed, our findings could have important diagnostic and therapeutic implications for the management of antisocial youth.

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J Am Acad Child Adolesc Psychiatry 1996 Aug;35(8):997-1008
Attention-deficit hyperactivity disorder and juvenile mania: an overlooked comorbidity?
Biederman J, Faraone S, Mick E, Wozniak J, Chen L, Ouellette C, Marrs A, Moore P, Garcia J, Mennin D, Lelon E
Pediatric Psychopharmacology Unit, Massachusetts General Hospital, Boston 02114, USA.
OBJECTIVE: To evaluate the psychiatric, cognitive, and functional correlates of attention-deficit hyperactivity disorder (ADHD) children with and without comorbid bipolar disorder (BPD). METHOD: DSM-III-R structured diagnostic interviews and blind raters were used to examine psychiatric diagnoses at baseline and 4-year follow-up in ADHD and control children. In addition, subjects were evaluated for cognitive, academic, social, school, and family functioning. RESULTS: BPD was diagnosed in 11% of ADHD children at baseline and in an additional 12% at 4-year follow-up. These rates were significantly higher than those of controls at each assessment. ADHD children with comorbid BPD at either baseline or follow-up assessment had significantly higher rates of additional psychopathology, psychiatric hospitalization, and severely impaired psychosocial functioning than other ADHD children. The clinical picture of bipolarity was mostly irritable and mixed. ADHD children with comorbid BPD also had a very severe symptomatic picture of ADHD as well as prototypical correlates of the disorder. Comorbidity between ADHD and BPD was not due to symptom overlap. ADHD children who developed BPD at the 4-year follow-up had higher initial rates of comorbidity, more symptoms of ADHD, worse scores on the CBCL, and a greater family history of mood disorder compared with non-BPD, ADHD children. CONCLUSIONS: The results extend previous results documenting that children with ADHD are at increased risk of developing BPD with its associated severe morbidity, dysfunction, and incapacitation.

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J Am Acad Child Adolesc Psychiatry 1996 Jun;35(6):826-828
A pharmacological approach to the quagmire of comorbidity in juvenile mania.
Wozniak J, Biederman J
Pediatric Psychopharmacology Unit, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.

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Arch Gen Psychiatry 1996 May;53(5):437-446
A prospective 4-year follow-up study of attention-deficit hyperactivity and related disorders.
Biederman J, Faraone S, Milberger S, Guite J, Mick E, Chen L, Mennin D, Marrs A, Ouellette C, Moore P, Spencer T, Norman D, Wilens T, Kraus I, Perrin J
Pediatric Psychopharmacology Unit, Massachusetts General Hospital, Boston, USA.
BACKGROUND: Previous cross-sectional data showed that children and adolescents with attention-deficit hyperactivity disorder (ADHD) are at increased risk of comorbid conduct, mood, and anxiety disorders as well as impairments in cognitive, social, family, and school functioning. However, longitudinal data were needed to confirm these initial impressions. METHODS: Using DSM-III-R structured diagnostic interviews and raters blinded as to diagnosis, we reexamined psychiatric diagnoses at 1- and 4-year follow-ups in children with ADHD and controls. In addition, subjects were evaluated for cognitive, achievement, social, school and family functioning. RESULTS: Analyses of follow-up findings revealed significant differences between children with ADHD and controls in rates of behavioral, mood, and anxiety disorders, with these disorders increasing markedly from baseline to follow-up assessments. In addition, children with ADHD had significantly more impaired cognitive, family, school, and psychosocial functioning than did controls. Baseline diagnosis of conduct disorder predicted major depression and bipolar disorder at follow-up, and anxiety disorders at baseline predicted anxiety disorders at follow-up. CONCLUSION: These results confirm and extend previous retrospective results indicating that children with ADHD are at high risk of developing a wide range of impairments affecting multiple domains of psychopathology such as cognition, interpersonal, school, and family functioning. These findings provide further support for the value of considering psychiatric comorbidity in both clinical assessment and research protocols involving children with ADHD.

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Biol Psychiatry 1996 Mar 15;39(6):458-460
Phenomenology and comorbidity of adolescents hospitalized for the treatment of acute mania.
West SA, Strakowski SM, Sax KW, McElroy SL, Keck PE Jr, McConville BJ
Biological Psychiatry Program, University of Cincinnati, College of Medicine, Ohio, USA.

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Psychopharmacol Bull 1996;32(1):63-66
Differences in thyroid function studies in acutely manic adolescents with and without attention deficity hyperactivity disorder (ADHD).
West SA, Sax KW, Stanton SP, Keck PE Jr, McElroy SL, Strakowski SM
Biological Psychiatry Program, University of Gincinati College of Medicine, OH, USA.
The purpose of this study was to compare basal thyroid indices in adolescent (ages 12 to 18) bipolar patients with and without attention deficit hyperactivity disorder (ADHD). On the basis of earlier studies, the authors hypothesized that bipolar patients with comorbid ADHD would have lower serum triiodothyronine (T3) and thyroxine (T4) concentrations and higher serum thyroid stimulating hormone (TSH) concentrations compared with patients with bipolar disorder alone. Thirty adolescents who met DSM-III-R criteria for bipolar disorder and were hospitalized for the treatment of acute mania were assessed. Twenty patients (66%) had comorbid ADHD. The mean serum T4 concentration in this group was significantly lower than it was for patients with bipolar disorder alone. There were no significant differences between groups in serum T3 or TSH concentrations. Although, these data are preliminary and require further investigation, this may have important implications regarding the potential benefits of thyroid supplementation in adolescents with bipolar disorder and comorbid ADHD who do not respond to mood stabilizers alone.

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Am J Psychiatry 1995 Dec;152(12):1793-1799
Attention deficit hyperactivity disorder and comorbid disorders: issues of overlapping symptoms.
Milberger S, Biederman J, Faraone SV, Murphy J, Tsuang MT
Pediatric Psychopharmacology Unit, Massachusetts General Hospital, Boston 02114, USA.
OBJECTIVE: Since some symptoms are shared by both attention deficit hyperactivity disorder (ADHD) and comorbid psychiatric conditions, it is possible that a diagnosis of ADHD is an artifact of the overlapping symptoms. This article focuses on the assessment of the influence of overlapping symptoms on the diagnosis of ADHD. METHOD: Three groups of subjects were studied: a group of clinically referred children and adolescents, a group of nonreferred adults who were the parents of these children and adolescents, and a group of clinically referred adults with ADHD. The authors assessed the extent of symptom overlap between ADHD and the disorders that frequently co-occur with ADHD; major depression, bipolar disorder, and generalized anxiety disorder. To determine the degree to which this symptom overlap influences these diagnoses, each individual was rediagnosed on the basis of two different techniques that corrected for the overlapping symptoms, a subtraction method and a proportion method. RESULTS: The majority of subjects who had both ADHD and a comorbid psychiatric disorder maintained their diagnosis of ADHD when the overlapping symptoms were subtracted. Moreover, when overlapping ADHD symptoms were subtracted, on average, 79% maintained their diagnosis of major depression, 56% maintained their diagnosis of bipolar disorder, and 75% maintained their diagnosis of generalized anxiety disorder. CONCLUSIONS: These findings show that ADHD is not an artifact of symptoms shared with other psychiatric disorders and that the comorbid conditions themselves are not an artifact of overlapping ADHD symptoms.

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J Am Acad Child Adolesc Psychiatry 1995 Jul;34(7):867-876
Mania-like symptoms suggestive of childhood-onset bipolar disorder in clinically referred children.
Wozniak J, Biederman J, Kiely K, Ablon JS, Faraone SV, Mundy E, Mennin D
Pediatric Psychopharmacology Unit, Massachusetts General Hospital, Boston 02114, USA.
OBJECTIVE: To examine the prevalence, characteristics, and correlates of mania among referred children aged 12 or younger. Many case reports challenge the widely accepted belief that childhood-onset mania is rare. Sources of diagnostic confusion include the variable developmental expression of mania and its symptomatic overlap with attention-deficit hyperactivity disorder (ADHD). METHOD: The authors compared 43 children aged 12 years or younger who satisfied criteria for mania, 164 ADHD children without mania, and 84 non-ADHD control children. RESULTS: The clinical picture was fully compatible with the DSM-III-R diagnosis of mania in 16% (n = 43) of referred children. All but one of the children meeting criteria for mania also met criteria for ADHD. Compared with ADHD children without mania, manic children had significantly higher rates of major depression, psychosis, multiple anxiety disorders, conduct disorder, and oppositional defiant disorder as well as evidence of significantly more impaired psychosocial functioning. In addition, 21% (n = 9) of manic children had had at least one previous psychiatric hospitalization. CONCLUSIONS: Mania may be relatively common among psychiatrically referred children. The clinical picture of childhood-onset mania is very severe and frequently comorbid with ADHD and other psychiatric disorders. Because of the high comorbidity with ADHD, more work is needed to clarify whether these children have ADHD, bipolar disorder, or both.

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Ann Clin Psychiatry 1995 Jun;7(2):51-55
Affective comorbidity in children and adolescents with attention deficit hyperactivity disorder.
Butler SF, Arredondo DE, McCloskey V
Innovative Training Systems, Inc., Amherst, New Hampshire 03031-1209, USA.
Recent research examining comorbidity associated with attention deficit hyperactivity disorder (ADHD) has raised the possibility of the existence of subtypes of the disorder. If this is the case, delineating subgroups is clinically imperative. Two hundred seventy nonrepetitive, consecutively admitted children and adolescent inpatients received structured diagnostic interviews (Schedule for Affective Disorders and Schizophrenia in School Aged Children). Twenty-eight percent of these children met the criteria for ADHD. Of those children with an ADHD diagnosis, 68% also met the criteria for an affective disorder. Thirty-six percent met the full criteria for major depression disorder. Eight percent met the criteria for an affective psychosis and 22% were diagnosed with bipolar disorder. There was a significant overlap between ADHD and bipolar disorder, suggesting the possibility of a lack of specificity in the diagnostic instruments used in this population. The results support the clinical necessity of carefully assessing for occult affective illness in all children and adolescents with attention deficit disorder.

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Res Dev Disabil 1995 May;16(3):221-231
Affective disorders in hospitalized children and adolescents with mental retardation: a retrospective study.
Johnson CR, Handen BL, Lubetsky MJ, Sacco KA
Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, PA 15213, USA.
We contrasted a sample of children and adolescents with affective disorders and mental retardation with a comparison group on behavioral symptoms, associated diagnoses, and psychopharmacologic treatment. Fifty consecutive patients with both impaired intellectual functioning and at least one affective disorder admitted to a psychiatric inpatient unit for children and adolescents with developmental disabilities and psychiatric disorders were matched to a group of 50 inpatients without depression. Behavioral symptoms such as suicidal ideation or gestures, crying, irritability, sleep problems, agitation, mood lability, and social withdrawal/isolation occurred significantly more often in the affective group than in the comparison group. Aggression, however, was the most frequent behavior concern for both groups, whereas disruption/destruction was identified significantly more often in the comparison group. Regarding Axis I diagnoses, the comparison group was more often identified with externalizing disorders (ADHD, ODD), though there was a high rate of comorbidity in the affective disorder group. The behavioral symptoms used to diagnosis normally developing children and adolescents appear to be applied in making affective disorders diagnoses in this sample of children and adolescents with mental retardation.

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Can J Psychiatry 1995 Mar;40(2):109-110
Rhinestones and gold-dust: attention deficit, borderline personality, or mood disorder?
Kubacki A

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Am J Psychiatry 1995 Feb;152(2):271-273
Attention deficit hyperactivity disorder in adolescent mania.
West SA, McElroy SL, Strakowski SM, Keck PE Jr, McConville BJ
Department of Psychiatry, University of Cincinnati College of Medicine, Ohio 45267-0559. OBJECTIVE: The purpose of this study was to examine the rate of attention deficit hyperactivity disorder in adolescents with bipolar disorder and to explore the potential effects of comorbid attention deficit hyperactivity disorder on the phenomenology of adolescent bipolar disorder. METHOD: The authors assessed the rate of attention deficit hyperactivity disorder for adolescents with bipolar disorder who were hospitalized for treatment of acute mania or hypomania. RESULTS: Eight (57%) of 14 adolescent bipolar patients also met DSM-III-R criteria for attention deficit hyperactivity disorder. Patients with both disorders were more likely to be male and Caucasian and to have mixed rather than manic bipolar disorder. Patients with attention deficit hyperactivity disorder had a higher mean total score on the Young Mania Rating Scale than patients with bipolar disorder alone. CONCLUSIONS: Although preliminary, these findings may have important implications regarding the potential relationship between bipolar disorder and attention deficit hyperactivity disorder.

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Child Psychiatry Hum Dev 1995;26(1):11-18
Comorbid disorders in hospitalized bipolar adolescents compared with unipolar depressed adolescents.
Borchardt CM, Bernstein GA
University of Minnesota Medical School, Minneapolis, USA.
This study examined comorbid psychiatric disorders in adolescents with bipolar disorder. Hospitalized bipolar adolescents (N = 10) were compared to hospitalized adolescents with unipolar depression (N = 33), and to adolescents with nonaffective psychiatric disorders (N = 11). Results showed conduct disorder, attention-deficit hyperactivity disorder, psychosis, and having any DSM-III-R psychoactive substance use disorder were all significantly more common in the bipolar group than the unipolar depressed group. Comorbid anxiety disorder was present in 40-45% of the subjects in the unipolar and bipolar groups, but in none of the control group subjects.

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Psychopharmacol Bull 1995;31(2):347-351
The comorbidity of attention-deficit hyperactivity disorder in adolescent mania: potential diagnostic and treatment implications.
West SA, Strakowski SM, Sax KW, Minnery KL, McElroy SL, Keck PE Jr
Department of Psychiatry, University of Cincinnati College of Medicine, OH, USA.
The frequency of attention-deficit hyperactivity disorder (ADHD) was assessed in 20 adolescents with DSM-III-R bipolar disorder hospitalized for the treatment of acute mania. Thirteen (65%) patients met DSM-III-R criteria for ADHD. Patients who met criteria for both disorders were more likely to be Caucasian and male, and to have mixed rather than pure mania. Patients with ADHD also had a higher mean total Young Mania Rating Scale score and lower serum thyroxine concentrations than patients with bipolar disorder alone. These results suggest that prior histories of ADHD or ADHD symptoms may be common in adolescents hospitalized for mania, and that patients with both disorders may have more severe manic symptoms than patients with mania alone. These findings may have important implications, especially in determining the optimal pharmacologic treatment of patients who meet criteria for both disorders, because standard treatments for ADHD and bipolar disorder have been assumed to exert opposing effects.

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J Am Acad Child Adolesc Psychiatry 1992 Jul;31(4):611-614
Difficulties in diagnosing manic disorders among children and adolescents.
Bowring MA, Kovacs M
Department of Psychiatry, University of Pittsburgh School of Medicine, PA.
Four factors are delineated that account for the difficulties in identifying and diagnosing manic disorders among children and adolescents. These factors are the low base rate of the disorder, its variable clinical presentation within and across episodes, its symptomatic overlap with more common disorders of childhood, and the constraints placed on symptom expression by the developmental stage of a child. Each of these factors is discussed in terms of its impact on the likelihood of recognizing mania, and strategies are proposed to improve diagnostic accuracy.

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J Clin Psychiatry 1992 Apr;53(4):133-136
Misdiagnosed bipolar disorder in adolescents in a special educational school and treatment program.
Isaac G
Division of Child Psychiatry, Nassau County Medical Center, East Meadow, N.Y.
BACKGROUND: Twelve adolescents found to be the most problematic, crisis prone, and treatment resistant were comprehensively reevaluated in the special educational day school and treatment program they were attending. This reevaluation took place over a 6-month period and was done to arrive upon a more comprehensive diagnostic understanding so that more relevant and effective treatment measures could be instituted. METHOD: The author conducted semistructured interviews with the adolescents on multiple occasions as the clinical situations warranted. All information available, recorded or otherwise, was comprehensively reviewed and reevaluated. The children were observed informally in and out of their classrooms throughout the period. All parents available were interviewed to clarify the children's present and past symptomatology and to assess the nature of psychiatric disorders, if any, in first- and second-degree family members. RESULTS: The reevaluation showed that 8 of the 12 youngsters clearly satisfied DSM-III-R criteria for bipolar disorder, which had been misdiagnosed mainly as attention-deficit hyperactivity disorder (ADHD) and conduct disorder. Three other youngsters showed significant bipolar features though not fully satisfying the criteria for this disorder. CONCLUSION: Bipolar disorder may be very common among highly problematic adolescents in special educational and outpatient treatment facilities for emotionally disturbed youngsters but may still be misdiagnosed very often as ADHD and conduct disorder, with all the negative consequences of such misdiagnosis.

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J Am Acad Child Adolesc Psychiatry 1992 Mar;31(2):262-270
The effects of methylphenidate and lithium on attention and activity level.
Carlson GA, Rapport MD, Kelly KL, Pataki CS
Department of Psychiatry and Behavioral Science, State University of New York, Stony Brook 11794-8790.
Seven psychiatrically hospitalized prepubertal children were treated with methylphenidate, placebo, lithium carbonate alone and in combination with methylphenidate. Children met DSM-III-R criteria for both disruptive behavior disorder and bipolar or major depressive disorder by structured interview and consensus diagnosis. Parents, children, teachers, staff, and raters were blind to medication condition. Children were rated weekly on measures of attention and activity to determine whether medications alone or in combination produced a differential effect on these variables. The nosological and practical implications of the results are discussed.

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Arch Gen Psychiatry 1991 Jul;48(7):633-642
Evidence of familial association between attention deficit disorder and major affective disorders.
Biederman J, Faraone SV, Keenan K, Tsuang MT
Pediatric Psychopharmacology Unit, Massachusetts General Hospital, Boston 02114.
With the use of family study methods and assessments by "blinded" raters, we tested hypotheses about patterns of familial association between DSM-III attention deficit disorder (ADD) and affective disorders (AFFs) among first-degree relatives of clinically referred children and adolescents with ADD (73 probands, 264 relatives) and normal controls (26 probands, 92 relatives). Among the 73 ADD probands, 24 (33%) met criteria for AFFs (major depression, n = 15 [21%]; bipolar disorder, n = 8 [11%]; and dysthymia, n = 1 [1%]). After stratification of the ADD sample into those with AFFs (ADD + AFF) and those without AFF (ADD), familial risk analyses revealed the following: (1) the relatives of each ADD proband subgroup were at significantly greater risk for ADD than were relatives of normal controls; (2) the age-corrected morbidity risk for ADD was not significantly different between relatives of ADD and ADD + AFF (27% vs 22%); however, these two risks were significantly greater than the risk to relatives of normal controls (5%); (3) the risk for any AFF (bipolar disorder, major depressive disorder, or dysthymia) was not significantly different between relatives of ADD probands and ADD + AFF probands (28% and 25%), but these two risks were significantly greater than the risk to relatives of normal controls (4%); (4) ADD and AFFs did not cosegregate within families; and (5) there was no evidence for nonrandom mating. These findings are consistent with the hypothesis that ADD and AFFs may share common familial vulnerabilities. ---------- Am J Psychiatry 1991 May;148(5):564-577
Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders.
Biederman J, Newcorn J, Sprich S
Pediatric Psychopharmacology Unit, Massachusetts General Hospital, Boston 02114.
OBJECTIVE: Attention deficit hyperactivity disorder is a heterogeneous disorder of unknown etiology. Little is known about the comorbidity of this disorder with disorders other than conduct. Therefore, the authors made a systematic search of the psychiatric and psychological literature for empirical studies dealing with the comorbidity of attention deficit hyperactivity disorder with other disorders. DATA COLLECTION: The search terms included hyperactivity, hyperkinesis, attention deficit disorder, and attention deficit hyperactivity disorder, cross-referenced with antisocial disorder (aggression, conduct disorder, antisocial disorder), depression (depression, mania, depressive disorder, bipolar), anxiety (anxiety disorder, anxiety), learning problems (learning, learning disability, academic achievement), substance abuse (alcoholism, drug abuse), mental retardation, and Tourette's disorder. FINDINGS: The literature supports considerable comorbidity of attention deficit hyperactivity disorder with conduct disorder, oppositional defiant disorder, mood disorders, anxiety disorders, learning disabilities, and other disorders, such as mental retardation, Tourette's syndrome, and borderline personality disorder. CONCLUSIONS: Subgroups of children with attention deficit hyperactivity disorder might be delineated on the basis of the disorder's comorbidity with other disorders. These subgroups may have differing risk factors, clinical courses, and pharmacological responses. Thus, their proper identification may lead to refinements in preventive and treatment strategies. Investigation of these issues should help to clarify the etiology, course, and outcome of attention deficit hyperactivity disorder.

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J Clin Psychiatry 1991 Apr;52(4):165-168
Bipolar disorder in prepubertal children in a special educational setting: is it rare?
Isaac G
Child Psychiatry Division, Nassau County Medical Center, East Meadow, N.Y.
The author undertook a comprehensive clinical reevaluation of five prepubertal children attending a special educational class for emotionally disturbed children in a day program. The children had failed to improve or had continued to worsen despite years of treatment in multiple settings. This extensive reevaluation and observation, spanning many months, revealed that all of the children met DSM-III-R criteria for bipolar disorder (lifetime prevalence). None of the children had been previously diagnosed with this disorder. The author's finding suggests that bipolar disorder may be more common in severely problematic prepubertal children than is generally recognized. The implications of this and related issues are discussed.

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J Am Acad Child Adolesc Psychiatry 1990 Jul;29(4):566-570
Atypical outcome in attention deficit hyperactivity disorder.
Schmidt K, Freidson S
Division of Child/Adolescent Outpatient Service, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York.
This report describes the course of psychiatric illness in two boys. Both presented with attention deficit hyperactivity disorder (ADHD) in midchildhood; after puberty, one boy developed a schizophrenic illness while the other boy developed a major affective illness. Although the major ADHD outcome studies have found no link between the childhood occurrence of ADHD and psychosis in adulthood, occasionally such a link may exist. The theoretical and practical implications of this finding are discussed. It should be noted, however, that such outcome is highly atypical and very rare.

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Can J Psychiatry 1989 Aug;34(6):526-529
Relationship between psychiatric illness and conduct disorder in adolescents.
Kutcher SP, Marton P, Korenblum M
Adolescent Inpatient Services, Sunnybrook Medical Centre.
Ninety-six psychiatrically ill adolescents admitted to an adolescent inpatient service were systematically assessed to determine the morbidity of conduct disorder (CD), with other Axis I psychiatric disorders. Twenty-six (27%) met DSM-111 criteria for CD in addition to other Axis I disorders. A CD diagnosis was significantly associated with substance abuse, and attention deficit disorder with hyperactivity. Although CD was found in 21% of depressives it was more commonly found in patients with psychotic disorders (25%) and bipolar (42%) disorders. These findings suggest that CD may be commonly found in a variety of adolescent psychiatric disorders. The implications of this finding for pharmacologic treatment of CD, the clinical assessment of the CD patient, and possible relationships between CD and adolescent psychiatric disorders are discussed.

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J Affect Disord 1988 Nov;15(3):219-226
Manic symptoms in a non-referred adolescent population.
Carlson GA, Kashani JH
Department of Psychiatry, State University of New York, Stony Brook 11794-8790. Using a structured interview with 150 randomly selected 14-16-year-olds and their parents, we found 20 who endorsed four or more manic symptoms of at least 2 days duration. Compared to the rest of the sample, these teenagers had significantly higher rates of attention deficit, conduct, and anxiety disorders and psychotic symptoms, and were seen as needing treatment by the interviewers. However, most of the pathology was endorsed by teenagers rather than parents. Other assessments confirmed this group as dysphoric, impulsive and emotionally labile. We discuss the normative and diagnostic implications of these findings though long-term follow-up is necessary to draw more certain conclusions.

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J Nerv Ment Dis 1987 Jul;175(7):431-432
Cocaine abuse, attention deficit disorder, and bipolar disorder.
Cocores JA, Patel MD, Gold MS, Pottash AC
Cocaine is a potent dopamine agonist that frequently stimulates the central nervous system and is often manifested by increased psychomotor activity, impulsivity, euphoria, and rapid thoughts. Attention deficit disorder (ADD) and bipolar disorder also present with physical restlessness, racing thoughts, distractibility, and mood instability. Although these three disorders rarely appear in the same individual, they are important differential diagnoses when considering any one illness with the above symptom complexes. We report two cases of cocaine abuse with ADD residual type in patients who were previously diagnosed as having atypical bipolar disorder. The adverse effects were reversed by the dopamine agonist bromocriptine.

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J Am Acad Child Adolesc Psychiatry 1987 May;26(3):381-388
Use of the personality inventory for children as an aid in differentiating children with mania from children with attention deficit disorder with hyperactivity.
Nieman GW, DeLong R

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Psychiatr Dev 1984;2(4):273-285
Classification issues of bipolar disorders in childhood.
Carlson GA
As systematic interviewing has become more widespread, it has been possible to identify significant populations of children and adolescents who meet adult criteria for depression. The difficulties associated with identifying correctly the phenomenology of major depression in children are reviewed. The significance of separation anxiety, anorexia, attention deficit and conduct disorder, as 'depressive equivalents' is discussed, although a change in mood or ability to experience pleasure appear to carry greater diagnostic weight. While the identification of mania and hence of bipolar disorder in children is more difficult, the appearance of a definite maniac syndrome in preadolescence is relatively uncommon. Data are reviewed suggesting the existence of an alternative and more common form of bipolar disorder in childhood, characterized by affective lability, irritability and explosive behavior. However, available data do not support the view that attention deficit disorder and 'emotionally unstable character disorder' are variants of bipolar syndromes.

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J Clin Psychiatry 1983 Apr;44(4):146-148
Pemoline and lithium in a patient with attention deficit disorder.
Brown RP, Ingber PS, Tross S

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Compr Psychiatry 1982 Nov;23(6):552-559
The under- and over-diagnosis of mania in children and adolescents.
Casat CD

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Am J Psychiatry 1979 May;136(5):702-706
Manic-depressive variant syndrome of childhood: a preliminary report.
Davis RE
The author describes the specific diagnostic entity of manic-depressive variant syndrome of childhood and outlines the five essential diagnostic criteria (affective storms, family history of significant affective dysfunction, hyperactivity, chronically disturbed personal relationships, and absence of psychotic thought disorder) and the five secondary criteria (sleep disturbances, minimal brain dysfunction, abnormal EEG, enuresis, and neuropathology). In the four cases reported, the children, when properly diagnosed, responded well to lithium therapy. The author points out the need for further study of this syndrome. Precautions about the use of lithium in children under age 12 are crucial, as is the need for continuing psychotherapy for parents and child.

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