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Bipolar Disorder and ADHD: Comorbidity and Diagnostic Distinctions

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Curr Psychiatry Rep
DOI 10.1007/s11920-015-0604-y
BIPOLAR DISORDERS (W CORYELL, SECTION EDITOR)
Bipolar Disorder and ADHD: Comorbidity
and Diagnostic Distinctions
Ciro Marangoni 1 & Lavinia De Chiara 1 & Gianni L. Faedda 2,3,4
# Springer Science+Business Media New York 2015
Abstract Attention-deficit/hyperactivity disorder (ADHD)
and bipolar disorder (BD) are neurodevelopmental disorders
with onset in childhood and early adolescence, and common
persistence in adulthood. Both disorders are often undiag-
nosed, misdiagnosed, and sometimes over diagnosed, leading
to high rates of morbidity and disability. The differentiation of
these conditions is based on their clinical features, comorbid-
ity, psychiatric family history course of illness, and response
to treatment. We review recent relevant findings and highlight
epidemiological, clinical, family history, course, and
treatment-response differences that can aid the differential di-
agnosis of these conditions in an outpatient pediatric setting.
Keywords Adolescent . Attention deficit-hyperactivity
disorder . Bipolar disorder . Child . Clinical features . Course .
Differential diagnosis . Treatment
This article is part of the Topical Collection on Bipolar Disorders
* Gianni L. Faedda
moodcenter@gmail.com
Ciro Marangoni
ciromarangoni@hotmail.com
Lavinia De Chiara
laviniadechiara@hotmail.it
1
Centro Lucio Bini, Via Crescenzio 42, 00193 Rome, Italy
2
Lucio Bini Mood Disorders Center, 245 East 50th Street, New
York, NY 10022, USA
3
Child Study Center, Department of Child and Adolescent Psychiatry,
New York University Medical Center, New York, NY, USA
4
International Consortium for Bipolar Disorder Research, McLean
Hospital, Belmont, MA, USA
Introduction
Attention-deficit/hyperactivity disorder (ADHD) and bipolar
disorder (BD) are highly prevalent neurodevelopmental disor-
ders with an early age of onset [1••], a chronic course, and
persistence into adulthood leading to significant impairment
of educational, vocational, and interpersonal functioning and
increased morbidity and mortality. BD and ADHD often co-
occur, and are commonly associated with other medical and
psychiatric conditions [2–5].
BD is a mood disorder with abnormal shifts in mood, en-
ergy, activity, sleep, and cognitive functions during episodes
of mania and depression. BD is often associated with anxiety,
behavioral and personality disorders, sub-stance abuse, high
rates of suicide, and excess mortality.
ADHD is defined by early onset (diagnosed before age 12
in the DSM-5) of persistent (6 months or longer) symptoms of
inattention and/or hyperactivity and impulsivity that is not
consistent with development, causing impairment of normal
functioning in at least two settings (home, school). ADHD is
the most common psychiatric disorder diagnosed in children,
mostly in school-age subjects, and the majority (75 %) are
males [6, 7], and rates have remained stable over time [8].
Great variability has been found in rates of ADHD in interna-
tional studies: in the USA, a range of methods (parents’ inter-
views, checklists, teacher’s reports) are accepted to make the
diagnosis of ADHD, and the level of expertise of clinicians
making this diagnosis varies a great deal (pediatricians, neu-
rologists, psychiatrists, psychologists, nurses), while in
Europe, only a specialist in child psychiatry can make the
diagnosis [6]. Furthermore, Diagnostic and Statistical
Manual of Mental Disorders (DSM) criteria allow for multiple
comorbidities, ADHD can be diagnosed with other diagnosis
like anxiety or depression with the DSM, while the
International Classification of Diseases (ICD)-10 hyperkinetic
 Page 2 of 9
disorder does not allow for comorbid diagnoses and signifi-
cant differences exist in the criteria used for the diagnosis, as
the ICD-10 requires both hyperactivity-impulsivity and inat-
tention criteria to be met; this might to be the cause for higher
rates of ADHD in the USA compared to the UK and other
Western countries [9, 10•].
ADHD and BD account for a large proportion of prescrip-
tions in preschoolers, both stimulants [11], and antipsychotic/
mood stabilizing agents [12]. Currently, we lack systematic
information not only on the causes of these disorders, but also
about the causes for their common under-, over- and misdiag-
nosis [7]. As these two clinical diagnoses cannot rely on any
biomarker and share many features in their manifestations, the
early recognition, accurate differentiation, and timely, appro-
priate treatment are public health priorities.
Our focus on differential diagnosis among pediatric and
young adult cases is justified by the early occurrence of
ADHD and BD; and the need for early diagnosis and treat-
ment; its greater importance for clinicians, public health pol-
icies, treatment, and prevention.
We conducted a selective review of the medical literature
on PubMED, to highlight epidemiological, clinical, family
history, course and treatment-response differences that can
aid the differential diagnosis of these conditions in an outpa-
tient pediatric setting.
The Differential Diagnosis of ADHD and BD
Few clinical challenges rival the differential diagnosis be-
tween childhood-onset behavioral disorder like ADHD and
BD. Without established biomarkers to aide the diagnostic
assessment, we rely on clinical observation and parental/
school reporting.
The differential diagnosis between ADHD and BD offers
several challenges, mostly related to the young age of onset of
both disorders, retrospective parental reports, the non episodic
course of BD in youths, the limited ability to self-report symp-
toms in pediatric samples, extensive symptomatic overlap,
reciprocal comorbidity, and similar psychiatric comorbidities
(anxiety, mood disorders, substance use disorder (SUD)).
In most cases of ADHD and BD, the differential diagnosis
is complicated by co-occurring disorders and complex comor-
bidities. In most uncomplicated cases, the discrete appearance
of prominent mood, sleep, and aggressive behaviors are more
likely to predict a diagnosis of BD, especially if impulsive
behavior is exhibited around money (spending); sex
(promiscuity); and substances (tobacco, alcohol, substances).
On the other hand, fidgeting and restlessness and inefficient
and disorganized performances stemming from inattentive-
ness, distractibility and forgetfulness, often point to ADHD
[13].
In the multimodal treatment study for ADHD, only a third
of the children in the study had ADHD only without comorbid
Curr Psychiatry Rep
conditions. More than 50 % had conduct disorder (CD) or
oppositional defiant disorder (ODD) besides ADHD, and
those with ODD and CD often had a comorbid anxiety disor-
der [13]. Less often, especially in girls, it is an inattentive form
of ADHD and a depressive phase of BD that must be
differentiated.
The greatest difficulties in the clinical differentiation of
ADHD from BD occur when ADHD is comorbid with CD
and/or ODD, as their presentation (temper tantrum, aggressive
behavior) can overlap with symptoms of a manic or mixed
state. Co-occurring ODD and CD in a child with ADHD
may increase the risk for verbal and physical aggression or
destruction of property and blur the boundaries between
ADHD and BD [14].
Epidemiology
In community studies, the prevalence of ADHD ranges from
1.7 to 16 % in school-age youths and 1–5 % of adults and is
the primary reason for mental health/behavioral or special
education [15, 16]. ADHD persists into adulthood, with one
third of the subjects diagnosed with ADHD in childhood
meeting full criteria as adults, but almost two thirds reporting
ongoing impairment because of ADHD symptoms [4, 17].
BD has an estimated lifetime prevalence of 2.1 % in adults
and a recent meta-analysis confirmed rates of 1.8 % in chil-
dren [18]. Among adults with BD, at least two thirds reported
the onset before the age of 18 [19, 20] and often manifest early
in the course of the illness with fewer, shorter, or attenuated
symptoms (BD-not otherwise specified (NOS)) [21••, 22].
The DSM-5 did not address developmental differences in
the manifestations of BD at different ages [23].
Both disorders are more prevalent in males (at least BD-I
and ADHD with hyperactivity), although ADHD-inattentive
type might be more common in girls. Estimates of persistence
in adulthood (transition from child to adult diagnosis) are well
documented for both disorders [4, 17, 19, 24–26].
BD youths tend to suffer from comorbid disorders, with
highest (weighted means) prevalence rate found for anxiety
disorders (54 %), ADHD (48 %), disruptive behavior (31 %),
and substance use (SUD) (31 %) disorders [5], ADHD and
anxiety comorbidity in pediatric BD negatively affects symp-
tomatology, cognitive, clinical, and global functioning [5].
Comorbidity between adolescent ADHD and CD, ODD,
anxiety disorders, or SUD significantly increase the odds of
developing later BD [27–29]. ADHD increases the risk of
developing substance abuse in both male and especially fe-
males [30, 31], while exposure to stimulants does not seem to
increase the risk of SUD unless CD is comorbid with ADHD
[32].
In clinical samples, children with ADHD are reported to
have an increased risk of comorbid BD [33, 34]. In more
Curr Psychiatry Rep
recent reports, the rates of comorbid ADHD in samples of
bipolar children [21••] and bipolar high-risk cohorts are not
elevated, except in offspring of adults with BD that were lith-
ium non-responders [35].
Clinical Features
The clinical differentiation of ADHD from manic or mixed
episode of BD has relied on three approaches. One approach
compares and contrasts the two syndromes by eliminating
overlapping symptoms. Elated mood, grandiosity, hypersexu-
ality, decreased need for sleep, racing thoughts, and all other
mania items except hyper-energetic and distractibility were
significantly and substantially more frequent among BD than
ADHD cases [33, 36]. Among BD groups, 55.0 % experi-
enced grandiose delusions, 26.7 % had suicidal behavior with
plan/intent, and 83.3 % had rapid, ultra-rapid or ultradian
mood cycles [36]. However, relying on non-overlapping
symptoms decreases the likelihood of contributing to the dif-
ferential diagnosis because of their relatively low prevalence.
Therefore, in all those cases free of psychotic, suicidal, or
hyper-sexual behavior, clinical differentiation remains
challenging.
An alternative and complementary approach used the chro-
nological appearance of symptoms on a developmental con-
tinuum in children with clinical or structured diagnosis of BD
and ADHD [37, 38]. This approach provided some evidence
f o r d i ff e r e n t i a l a n d i n d e p e n d e n t t r a j e c t o r i e s o f
psychopathology.
Using a parents’ survey of 37 common child psychopathol-
ogy symptoms of DSM-IV’s childhood-onset disorders,
Fergus [37] studied a community sample of youths with BD,
various psychiatric diagnoses (including major depression,
ADHD, CD, ODD, OCD, and Tourette’s syndrome), or with-
out a psychiatric diagnosis.
Temper tantrums, poor frustration tolerance, impulsivity,
increased aggression, decreased attention span, hyperactivity,
and irritability, began to distinguish bipolar children from the
others the earliest (i.e., from ages 1 to 6); symptoms more
typical of adult depression, mania, and psychosis, distin-
guished the children with a bipolar diagnosis from the others
much later (between ages 7 and 12). The same group [38] used
retrospective yearly ratings of symptoms in outpatients with
KSADS diagnoses of BD and ADHD, to identify symptoms
(or clusters) likely to discriminate between the two disorders
at an early age. Brief and extended periods of elevated mood
differentiated BD from ADHD cases as early as age three,
increasing over the first 10 years of ratings. Additionally, se-
vere irritability, decreased sleep, and inappropriate sexual be-
haviors (but not racing thoughts or depressive symptoms)
were early discriminators; sadness, changes in appetite, and
suicidal ideation were useful in discriminating BD from
Page 3 of 9
ADHD only around age 7. Further, night terrors, bedwetting,
and physical complaints were more frequent in BD than
ADHD cases. Hyperactivity, impulsivity, and short attention
span were not likely to discriminate between groups, and nei-
ther were symptoms of anxiety, OCD, or poor frustration
tolerance.
In the third approach, Child Behavior Checklist (CBCl)
scores in children with either BD or ADHD were compared
to assess how well CBCl could differentiate the two condi-
tions. A proxy for BD with an elevation of the anxious/de-
pressed, aggressive behavior, and attention problems sub-
scales (often referred to as CBCl-dysregulation profile) has
been found to accurately differentiate BD from ADHD [39,
40], but other studies found that this proxy was not specific to
BD, even though subjects with BD were more likely than
ADHD to have the CBCl-dysregulation profile [41, 42]
(Table 1).
Differences in Specific Symptoms
Hyperactivity
BD is often manifested with chronic or intermittent periods of
intense hyperactivity or agitation, often with increased impul-
sivity and aggression. Increased drive and interest, insomnia,
impulsivity, and grandiosity can all contribute to increased
levels of activity and even greater productivity, with rapid
transitions to new and more stimulating projects. Along with
peaks of activity and agitation, in BD, one can observe periods
of low activity, exhaustion and Bboredom.^
Instead, in children with ADHD, the demands of the class-
room might increase restlessness, fidgeting, and hyperactive
behavior, especially when the child is expected to engage in
structured activities requiring focus and prolonged effort.
Additionally, the temporal distribution of hyperactivity can
be helpful in differentiating the two conditions: in BD, circa-
dian rhythms are altered, resulting in greater fluctuations of
energy and activity, from very high to very low, as well as a
preference for evening hours often referred as Beveningness,^
with improved mood and energy in the later part of the day,
preceding and often interfering with sleep [43]. In ADHD, the
high, but relatively stable levels of locomotor activity can be
quite different from the fluctuating activity levels of a
bipolar child [44]. The real extent of symptomatic over-
lap between the hyperactivity of children with ADHD, BD, or
both remains poorly quantified, although actimetry measures
appear to be a promising aid in the differential diagnosis.
Actigraphy recordings in youth with ADHD, BD, both
(ADHD + mood), or neither showed numerous activity differ-
ences between normally developing controls and both chil-
dren with BD and children with ADHD without comorbid
mood disorders [44].
 Page 4 of 9 Curr Psychiatry Rep

Table 1 Differential diagnosis of BD-manic/mixed and ADHD-hyperactive type

Bipolar disorder ADHD

Presence of aggression and lack of remorse. Sometimes sadistic. Violence Non-angry destructiveness. Breaks things carelessly. Kid might bump into
and destruction to physical property common. Child will often lie about another kid but it’s due to inattention or poor special skills. Unaware of
hitting another child or can perceive imaginary threats consequences of actions, lacks ability for long-term planning or
consequences
Severe temper tantrums, can last >1 h Temper tantrums are brief, less intense
Misbehavior feels intentional and provocative. Sometimes described as Misbehavior often accidental caused by oblivious inattention
Bthe bully in the playground^
Stimulation seeking to avoid boredom Stimulation/thrill seeking
Engages in risk seeking behavior due to impaired judgment, impulsivity Engages in behavior that leads to harmful consequences but is often
and manic disinhibition unaware of the danger until the consequence occurs
Underestimates known risk Not aware of risks until asked
Can feel angry for longer periods of time, holds a grudge, unforgiving Can calm down usually in 20–30 min, can forget the reason for being upset
Rigid, inflexible, anxious Poor time management, late, tardy
Can voice violent, homicidal threats Voices frustration and anger
Thinking is often disorganized with crouched or fetal position Outburst generally less severe and shorter, without regressive behaviors
Amnesia of outburst and behavior is common Usually no amnesia of events
Trigger: limit setting, sleep deprivation, hypoglycemia, dehydration, heat, Tantrums usually triggered by difficulty with tasks (learning) or demands
emotional overstimulation on directed attention
Pressure of speech due to flight of ideas and vivid imagination, excitement Talkative due to lack of inhibition, may be sometimes redirected
Fluctuation in activity level throughout the day. Often low energy in the Hyperactive and/or inattentive all day, worse when prolonged attention or
morning, more energy at lunch, low energy in the afternoon and hyper in on-task behavior is expected
the late afternoon and evening
Sleep difficulties with difficulty getting to sleep or awakening during the Generally good sleepers. Normal circadian rhythm
night
Decreased need for sleep No decreased need for sleep
Sleep disturbance includes nightmares or night terrors. Often themes show Sleep resistance, less sleep disturbance unless related to comorbid sleep
explicit gore or body mutilation disorder
Sleep inertia, slow awakening, unless in a manic phase. Often irritable in Tend to arouse quickly and are alert in minutes
morning with dysphoria, fuzzy thinking, Bcobwebs^ and varieties of
somatic complaints such as headaches and stomachaches
Mood often dysphoric. Irritability is prominent symptom especially on Generally do not have dysphoric mood as predominant symptom. Mood
morning arousal. Very slow to attain morning alertness shifts usually related to demands of learning. Irritability is often
worsened by stimulant’s withdrawal
Rapid shifts of mood, no insight Less emotional variability, mood shifts
Cognitive giftedness, often verbally precocious and verbally advanced for Can be precocious but can also have learning disabilities
age
Self-esteem fluctuates from high to low Usually self-esteem worsens over time
Strong early sexual interest and behavior No precocious sexual interest in ADHD
Can present with psychotic symptoms No psychotic symptoms
Often exhibit gross distortions in perception of reality and interpretations of Do not exhibit psychotic symptoms or reveal loss of contact with reality
emotional events
Can have suicidal ideas/behavior Rare suicidal ideation/behavior
Lithium/mood stabilizers help symptoms Lithium/mood stabilizers have no effect
Antipsychotics improve symptoms Antipsychotics are ineffective
Stimulants can disrupt sleep/mood Stimulants are effective

Disturbances of Sleep and Circadian Rhythms
Frequent fluctuations of energy levels, including so-called ul-
tra rapid cycling, are well-documented features of mood dis-
orders in general and of BD in youths especially [44–46].
Increased daytime and nighttime hyperactivity disrupt
circadian rhythms and affect behavior and sleep, as document-
ed by clinical and objective measures [47, 48].
Early insomnia and sleep resistance have been reported in
both ADHD and BD, so their value in differentiating these
two conditions is limited [48, 49]. More useful are middle
and late insomnia, commonly observed among mood-
Curr Psychiatry Rep
disordered children rather than in ADHD cohorts [44].
Specifically, parasomnias, reduced total sleep time,
fragmented sleep, and enuresis are more often reported in
children with BD [38, 48].
Mood, Suicidality, and Psychosis
Mood symptoms are prominent in BD, but mood fluctuations
and dysregulation are common in children and adolescents
with ADHD, both with and without a co-occurring mood dis-
order [50]. A long history of severe irritability, dysphoria,
crying spells, temper tantrums, and mood lability have been
described as precursors of BD, especially in early onset BD
[37, 45, 47]. These can range from subsyndromal mood labil-
ity to cyclothymia and BD-NOS, and can have a significant
time depth, occurring years before full criteria for a mood
disorder are met [51]. In ADHD children, mood symptoms
tend to be secondary to academic or social difficulties, or
cluster around bedtime resistance [49], but in the absence of
Breduced need for sleep.^
Suicidality, including morbid (death) ideation, suicidal ide-
ation, and attempts are common in children and adolescents
with mood disorders in general and in BD especially [52].
Suicidality was a discriminating feature between children with
community psychiatric diagnoses of BD, ADHD, or other
disorders, but only after age 9 [37]. ADHD increased the risks
of attempted and completed suicide, even after adjusting for
comorbid psychiatric disorders (odds ratio (OR)=3.62 [95 %
confidence interval (CI), 3.29–3.98] and 5.91 [95 % CI, 2.45–
14.27], respectively) [53]. Psychosis, including delusions, hal-
lucinations, catatonic features, and bizarre behavior occurs
frequently in youths with BD [21 Birmaher 2009], but not in
ADHD.
Aggressive and Hypersexual Behavior
Various forms of aggression (verbal aggression, anger
dyscontrol, violent behavior leading to destruction of property
or physical aggression) are relatively common in BD [54].
Aggression can present in the course of severe temper tan-
trums, or as deliberate, planned aggression, sometimes with
lack of remorse. In ADHD, verbal and physical aggression
can result from irritability while the destruction of property
is accidental, related to inattention, impulsivity, and poor co-
ordination or impaired motor skills.
An increased and precocious interest in sexual images/
content or nudity, as well as increased sexual behaviors (both
self-stimulation and towards others) has been described in
some children and adolescents with BD [45, 55]. Depending
on the age, sexually provocative clothing, make-up, language,
and behaviors including but not limited to acquiring or view-
ing pornographic material, self-stimulation or sexualized play
with siblings, peers, and sometimes pets can be quite upsetting
Page 5 of 9
to parents, teachers, and peers. In such cases of inappropriate-
ly precocious sexualized behavior, it is extremely important to
rule out any kind of inappropriate exposure to adult material or
sexual abuse. While this symptom is not common, its presence
beyond normative development should be thoroughly inves-
tigated as a possible element of differentiation. Hypersexual
behavior is not part of the ADHD clinical presentation.
Academic Functioning
In children with ADHD, difficulties with inattention, resis-
tance to completing homework, and poor concentration often
interfere with academic achievement consistently over time
and across subjects. In contrast, children with BD are more
likely to have more variable, uneven performances, at times
doing very well, and then experiencing significant changes in
grades coinciding with periods of emotional instability and
especially depressive phases or periods of increased anxiety
and school refusal. Somatic complaints are frequent in chil-
dren with depression and have been found to predict suicide
attempts, BD, psychosis, as well as recurrent and chronic de-
pression [56]. As both diagnoses can be associated with learn-
ing disorders, a thorough neuropsychological assessment can
help provide adequate accommodations and support.
Family History
The most significant risk factor for developing BD is a posi-
tive family history [57]. Studies published since 1960 suggest
that the recurrence risk for BD in first-degree relatives of BD
patients is approximately 9 %, nearly ten times that of the
general population [58].
Twin studies have clearly established that the familiality of
BD is predominantly due to genetic influence. The heritability
of BD ranges from 58 [59] to 85 % [60]. Adoption and twin
studies estimate that 60–80 % of the risk for ADHD is herita-
ble, likely reflecting a polygenic or oligogenic risk mechanism
[61].
A meta-analyses based on 6238 relatives in pediatric bipo-
lar I family studies and 3478 relatives in ADHD family stud-
ies, found a significantly higher prevalence of ADHD among
relatives of bipolar I probands (27 % for offspring and 30 %
for siblings), and a significantly higher prevalence of bipolar I
disorder among relatives of ADHD probands (6.8 % for off-
spring, 5.9 % for siblings, and 5.1 % for parents) [57, 62•].
Course
The correct differentiation of children with BD from those
with ADHD is essential, as existing pharmacological interven-
tions can be costly and potentially dangerous. There is
 Page 6 of 9
evidence that both BD and ADHD may be under diagnosed,
over diagnosed, as well as misdiagnosed [7, 19, 63].
Many of the symptoms characteristic of ADHD and BD
represent the severe end of a spectrum of behaviors; emotional
and cognitive states that are common in children and adoles-
cents. For instance, hyperactivity might be developmentally
normal, and delays in achieving developmental milestones
can be misunderstood as symptoms of a deficit, or a disease,
if not properly evaluated in the context of other developmental,
socio-emotional, and cognitive tasks. In those cases where the
symptom (i.e., mood lability) is below the diagnostic threshold,
the clinician has to determine (1) that a sign/symptom repre-
sents a change from baseline, (2) that it is not explained by
situational factors, (3) that is not due solely to a developmental
delay, and (4) that it follows an independent course.
Only a minority of BD cases onset without any previous
psychopathology, while the majority experience temperamen-
tal (dysthymic or cyclothymic) mood symptoms long before
their first episode [51]. The Bpremorbid^ baseline, rather than
symptom-free, is often quite symptomatic, as transitional and
prodromal states are common in all mood disorders, especially
in youths [45, 51]. Longitudinal studies of BD in adult and
pediatric populations frequently follow a chronic course alter-
nating syndromal and subsyndromal phases with symptom-
free intervals [21••]. In BD, the episodic course (with multiple
recurrences of mania and depression and symptom-free inter-
vals) is only one of many courses of illness. Some patients
may experience chronic, unremitting symptoms, while other
patients may experience weeks or months with attenuated
symptoms, or symptom-free intervals [21••, 22, 64]. As evi-
denced by prospective research on the precursors of bipolar
disorder, attenuated symptoms of mania and depression often
transition into BD-NOS, sometimes progressing to BD-I or
BD-II [21••, 51]. In fact, the requirement of periodicity (recur-
ring episodes) to diagnose BD has often resulted in the mis-
diagnosis of those youths with a chronic, non-episodic course
of illness.
ADHD follows a chronic and unremitting course, and does
persist into adulthood in half of the cases [65]. Several predic-
tors of ADHD persistence into adulthood have been reviewed:
the persistence and severity of ADHD during development
were associated with adult antisocial and criminal behaviors
[4]. Among hyperactive-impulsive forms, ADHD was associ-
ated with trajectories of improvement while inattentive type
was often associated with negative outcomes [66]. While
symptoms of hyperactivity improved over time, inattention
did not improve or got worse [13, 67].
A 33-year prospective follow-up of children diagnosed
with ADHD at mean age 8 found they had worse educational,
occupational, economic, social, and marital outcomes than
non-ADHD comparisons [26]. Persistence of ADHD, antiso-
cial personality disorder, and SUD were also common.
Lifetime, they had more psychiatric hospitalizations and
Curr Psychiatry Rep
incarcerations than comparisons. Psychiatric disorders with
onsets at age 21 or older were not different between groups,
and the impairment predicted by ADHD in childhood started
in adolescence, usually before the age of 20 years [26].
Treatment Response
Stimulants prevent the reuptake of dopaminergic and noradren-
ergic systems implicated in cognitive deficits like poor
response-inhibition and impaired working memory.
Stimulants are helpful in reducing the impact of these deficits
on academic performance and social interaction, improve class-
room behavior, and increase time on task. Although stimulant
use is associated with academic improvements over short-term
follow-up, the MTA study failed to document long-term aca-
demic benefits of stimulant treatment. Large-population studies
have documented reduced criminal behavior in ADHD adults
and decreased car accidents in males with ADHD [17].
The number of prescriptions has increased by 1600 % over
9 years, with more than 8 million prescriptions in 2000 [61]. In
spite of the widespread use of stimulants in pediatric and adult
population, the effects of acute exposure during development
and chronic exposure in youths and adults are poorly under-
stood [68] and more research is required to assess safety, es-
pecially because of the extent of abuse [69•, 70], although
several studies suggest relative safety in patients with
ADHD compliant with treatment [17]. Additionally, as shown
by research in rodents and non-human primates, additional
damage may result from repeated withdrawal and abstinence
[61]. Amphetamines can cause psychotic symptoms of schizo-
phrenia in asymptomatic schizophrenics and in most healthy
human subjects at doses between 55 and 75 mg. After an
episode of amphetamine-induced paranoid psychosis, para-
noid symptoms can be triggered by psychosocial stress or by
amphetamine exposure. This phenomenon, known as behav-
ioral sensitization, is probably mediated by catecholaminergic
supersensitivity [61].
Therapeutic approaches are often quite different depending
on the primary diagnosis, but when BD and ADHD are co-
morbid, a combination of treatment is often required. For in-
stance, mood-stabilizing agents and atypical antipsychotic
may be beneficial for children with early onset BD but are
unlikely to enhance attention in children with ADHD and
can be associated with serious side effects [71, 72]. On the
other hand, stimulants have been shown to be ineffective in
the treatment of BD, can cause disruption of sleep and circa-
dian rhythms, and negatively affect subjects with BD, based
on retrospective and prospective reports [73, 74]. In a recent
study of 22,797 cases diagnosed with pediatric ADHD, the
odds of developing BD were significantly and positively as-
sociated with longer treatment with methylphenidate, mixed
amphetamine salts, or atomoxetine (aOR=1.01) and being
treated with certain antidepressant medications, most notably
Curr Psychiatry Rep
fluoxetine (aOR=2.00), sertraline (aOR=2.29), bupropion
(aOR=2.22), trazodone (aOR=2.15), or venlafaxine (aOR=
2.37) prior to the first diagnosis of mania [28•]. In two outpa-
tient cohorts in the USA, the development of BD was ob-
served in 29 or 28.5 % of ADHD youths followed over 6–
10 years [75, 76], although in several pediatric BD + ADHD
trials, stimulants added to mood-stabilizers did not result in
manic exacerbation [77].
Conclusions
BD and ADHD share more than overlapping symptoms: sim-
ilar ages of onset and comorbidities, a chronic, lifelong course
of illness with disruption of educational, vocational, and es-
pecially developmental milestones sets the stage for signifi-
cant morbidity and mortality. For both disorders, evidence of
diagnostic error has been documented.
The clinical differentiation of ADHD and BD in youth
offers several challenges. For instance, developmental vari-
ability, extensive clinical overlap between diagnoses, limited
ability to self-report, and variable course of child psychopa-
thology (from complete remission to chronicity) have created
obstacles to clinical differentiation. Research priorities include
clarifying the longitudinal course, understanding family histo-
ry and environmental risk factors, and predicting treatment
response [78]. As both conditions have a negative impact on
public health and add to the cost to society, clinical tools have
failed to consistently differentiate ADHD from BD. Clinicians
need to avail themselves of any available data from epidemi-
ology and family history to clinical features, comorbidity, and
course of illness. The development of biomarkers (genetic,
imaging, behavioral, biological) will help distinguish ADHD
and BD, especially when complex comorbidities further com-
plicate the differential diagnosis. Like in other fields of medi-
cine, combining clinical with objective measures (biomarkers)
could greatly improve treatment selection and outcome.
Limitations
Limitations of this report include: non-systematic literature
review; focus on clinical features does not include a review
of findings from cognitive, neuropsychological, and neuroim-
aging studies, as they are often unavailable to clinicians; med-
ical and psychiatric comorbidity and family risk studies have
been reviewed extensively elsewhere [6, 35].
Compliance with Ethics Guidelines
Conflict of Interest Ciro Marangoni and Lavinia De Chiara declare
that they have no conflict of interest.
Gianni L. Faedda has received royalties for book: BParenting a Bipolar
Child^, New Harbinger Publishing, CA.
Page 7 of 9
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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