Curr Psychiatry Rep (2014) 16:516 DOI 10.1007/s11920-014-0516-2

BIPOLAR DISORDERS (W CORYELL, SECTION EDITOR)

Distinguishing Bipolar Disorder From Other Psychiatric Disorders in Children Manpreet K. Singh & Terence Ketter & Kiki D. Chang

# Springer Science+Business Media New York 2014

Abstract Pediatric onset bipolar disorder (BD) is a challenging diagnosis with potentially debilitating outcomes. This review aims to critically evaluate recently published literature relevant to the diagnosis of BD in youth, emphasizing interesting and important new findings characterizing pediatric BD and reporting updates in the diagnostic and statistical manual relevant to this disorder in youth. Challenges regarding the diagnosis of BD will be discussed, in addition to important distinctions with other childhood disorders, including other bipolar spectrum disorders; major depressive disorder; dysthymia; disruptive mood dysregulation disorder (DMDD); attention-deficit/hyperactivity disorder (ADHD) and other disruptive behavioral disorders; anxiety disorders, including post-traumatic stress disorder (PTSD); psychotic disorders; autism spectrum disorders; substance use disorders; and borderline personality disorder. The review concludes with a comment on past research limitations and future directions in the field. Keywords Pediatric bipolar disorder . Bipolar spectrum . Depression . ADHD . Anxiety . Mood dysregulation

Introduction The onset of bipolar disorder (BD) commonly occurs in childhood, as up to two thirds of adults with BD experience their first mood episode before age 18 [1]. Thus, the pediatric onset of BD has become more clinically recognized and has This article is part of the Topical Collection on Bipolar Disorders M. K. Singh (*) : T. Ketter : K. D. Chang Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Stanford, CA 94305-5719, USA e-mail: [email protected]

gained investigative interest in recent years. BD is a commonly debilitating disorder associated with multiple cognitive, emotional, social, and academic impairments; comorbidities; legal problems; and suicidal or self-injurious behavior [2, 3]. Diagnosing pediatric BD can be challenging due to differing clinical presentations compared with adults and symptom overlap with other childhood disorders. In this review, we discuss important distinctions between BD and other disorders and critically evaluate recent advances in the field. Compared to adult BD, pediatric BD is typically characterized by a more chronic course and more mixed/rapid cycling symptoms. Further, there is a higher risk of BD in firstdegree relatives of youth with BD than in first-degree relatives of adults with BD, which may indicate a greater genetic component in pediatric compared to adult BD [4]. In fact, youth with a familial risk for BD are at high risk for a variety of psychiatric disorders besides major mood disorders, including attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders [5, 6]. Moreover, youth with bipolar disorder “specified other” or “unspecified other” [in DSM-IV termed bipolar disorder not otherwise specified (BD-NOS)] and a family history of BD are more likely to convert to bipolar I disorder (BD-I) on longitudinal follow-up [7] compared to youth with bipolar disorder specified other or unspecified other but no BD family history, suggesting that family history is a key risk factor for the early development of BD. The differing clinical presentation between youth and adults complicates the diagnosis of pediatric BD [8–12], which can impact its reported incidence and prevalence. The prevalence of pediatric or adult bipolar spectrum disorders in the community is estimated to be 1.7–2.5 % [13–15]. Despite a relatively stable 1 % incidence of pediatric BD-I, recent evidence suggests that pediatric bipolar spectrum diagnoses in the USA are increasing [15], with a 40-fold increase in pediatric BD office visits from 1994 to 2003 [16] and a 2-fold increase in adolescent mania [15]. This increase in pediatric

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BD in the USA may reflect a true increase in prevalence (a cohort effect), improving recognition of pediatric BD, or an increasing problem with overdiagnosis [17]. The rising trend in pediatric bipolar diagnoses has not been observed internationally. A recent study also suggests that parental history of BD and both parents with a mood disorder were more common in the USA than in Europe and were associated with an early onset of bipolar disorder and other poor prognosis characteristics [18]. Greater genetic/familial loading for bipolar illness in the USA compared with Europe may explain why a more adverse course of BD has been observed in the USA [19]. From 2000 to 2010, discharge rates for pediatric bipolar spectrum disorders were found to be 12.5 times higher in the USA than in England [20]. European retrospective recall studies have reported older ages of onset of BD [21], which could indicate that there are simply more youth in the USA with fully developed BD [20]. Delays in diagnosis, misdiagnosis [22], differing definitions of BD [23], varying amounts of available epidemiological data, and varying levels of clinician recognition of and bias against the disorder could contribute to differing international prevalence statistics. There may also be less triggering (i.e., referring to the underlying etiology) of pediatric BD in Europe due to less stimulant and antidepressant use [24]; however, the idea that these medications trigger pediatric BD has not been fully substantiated [25]. Indeed, bipolar symptoms may have several potential underlying etiologies that are yet to be fully understood. Research investigation of these etiologies that support the brain basis of the disorder may reduce stigma and dispel the notion that BD is triggered by some exogenous factor. In fact, clinical definitions of BD require that a manic episode must not occur in the context of a medication-induced adverse event, even though certain medications may trigger bipolar symptoms either transiently or permanently. Etiologies of BD are particularly challenging to discern in youth in the context of dynamic changes in neurodevelopment. Longitudinal studies that follow youth with bipolar symptoms into adulthood will aid in clarifying etiological origins of BD symptoms and their lifelong impact. Diagnostic Challenges and Possible Reasons for Misdiagnosis Factors that contribute to misdiagnosis in pediatric BD include a high rate of comorbidity with disruptive behavioral disorders, such as ADHD [4], conduct disorder (CD), and oppositional defiant disorder (ODD) [26]. In addition, youth and caregivers may report different symptoms [27], which could lead to inaccurate diagnoses if clinicians rely only on child report alone. Furthermore, manic and hypomanic symptoms in a depressed child that do not cause significant impairment

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often go unnoticed [28], while mood and inattention symptoms may evolve with development. As such, symptoms of ADHD may represent precursor symptoms to a manic episode [29, 30]. Youth with BD-I have recently been found to exhibit a long, slow-onset mania prodrome that includes depressive and subthreshold manic symptoms [31•]. Thus, it may be possible to prospectively identify symptoms that precede the first manic episode using scales such as the Bipolar Prodrome Symptom Interview and Scale-Prospective (BPSS-P) [32]. Indeed, due to concerns about overdiagnosis, some community clinicians may opt for diagnoses like bipolar disorder specified other or unspecified other when there are uncertainties regarding symptoms [33]. DSM-5 Criteria for Pediatric Bipolar Disorder In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), BD-I is characterized by a significant period of irritability, euphoria, expansiveness, and increased goal-directed activity or energy, with or without periods of depression, that is distinct from the youth’s typical mood state [34, 35]. These can be distinct periods of mania or depression, or mania and depression symptoms may overlap (i.e., mixed states), and youth may have a fluctuating course of symptoms. Chronic symptoms that existed prior to the episode and that do not worsen during the episode should not be counted toward a bipolar diagnosis [35]. Disruptive mood dysregulation disorder (DMDD) is a new DSM-5 mood disorders diagnosis [34] that aims to decrease the overdiagnosis of pediatric BD and consequent overexposure of youth to medications with substantial side effect risks, such as second-generation antipsychotics [36]. DMDD encompasses children ages 6–18 with significant mood dysregulation who do not meet full criteria for BD-I or BD-II. Symptoms must onset before age 10, including a persistent irritable or angry mood and severe and recurrent temper outbursts. Those who support the inclusion of DMDD in the DSM-5 argue that it may identify youth without high rates of familial BD who are more at risk for unipolar depressive and anxiety disorders than BD [36]. However, it may not be possible to distinguish DMDD from other psychiatric disorders in youth, such as disruptive behavioral disorders, and it may be a diagnostically unstable disorder [37•]. Furthermore, DMDD may not be associated with current, future, or a parental history of mood or anxiety disorders [37•]. If this is true, children currently diagnosed with CD or obsessive-compulsive disorder could receive a DMDD diagnosis, and it could be used to medicate “difficult children” despite lacking evidence. Clearly, more research is needed to verify or refute the utility of this diagnosis.

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The Bipolar Spectrum as a Dimensional Approach to Classifying Youth One conceptualization of bipolar disorders is to view diagnoses on a spectrum, from BD-I, to BD-II, to bipolar disorder specified other or unspecified other, to unipolar major depressive disorder (MDD) [38, 39]. This may help to curb overdiagnosis of unipolar MDD at the expense of underdiagnosis of BD, particularly in adults [39]. However, the bipolar spectrum concept in youth is an area of particular controversy, as it may lead to an overdiagnosis of pediatric BD in marginal cases, particularly when depression or ADHD with a family history of BD is included within the spectrum [40]. The multicenter Longitudinal Assessment of Manic Symptoms (LAMS) study aims to assess mania dimensionally over time in order to identify clinical and neurobiological markers that differentiate diagnostic categories or that are associated with emotional and behavioral dysregulation dimensions [41•]. Approximately 85 % of youth in the LAMS study with high levels of manic symptoms at baseline exhibited decreasing manic symptoms over 24 months, while 15 % experienced unstable or increasing manic symptoms, suggesting nonuniform outcomes in youth with manic symptoms [42]. Neuroimaging results showed that independent of diagnosis, emotional and behavioral dysregulation was associated with increased left middle prefrontal cortical activity during the win condition of a reward paradigm, which may reflect increased reward sensitivity in these youth. Disruptive behavioral disorders were associated with decreased lower left ventrolateral prefrontal cortex activity during the win condition, suggesting that both diagnostic and dimensional aspects of mania may inform the neurobiology of BD. Longitudinal Course of Bipolar Spectrum Disorders Bipolar spectrum disorders are commonly enduring, with symptoms that commonly persist, progress, and/or recur [43]. In a multicenter study of youth with bipolar spectrum disorder, 40 % experienced syndromal or subsyndromal symptoms for three quarters of the 4-year study duration [44]. Chronic mixed symptoms (46 %) and symptoms of depression (33.8 %) were more prevalent than that of symptoms of mania or hypomania (21 %), and almost 40 % of those with bipolar disorder specified other or unspecified other converted to BD-I or BD-II. Over 80 % of participants recovered from their first episode, but almost two thirds experienced recurrent syndromal episodes, particularly depressive episodes. Factors associated with worse outcomes included a diagnosis of bipolar disorder specified other or unspecified other, long illness duration, early onset, low socioeconomic status, and family history of mood disorders. Recent evidence

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suggests that although approximately 60 % of youth with bipolar spectrum disorders are predominantly (24.0 %) or moderately (34.6 %) euthymic over a longitudinal trajectory, the other approximately 40 % remain predominantly ill (22.3 %) or ill with improving course (19.1 %) [45•]. From preadolescence to adolescence in youth with BD, there is an inverse linear relationship between age and motor activity, aggression, and irritability [46, 47], while symptoms of depression increase with age [47]. Pediatric BD-I in girls and boys has similar clinical correlates, comorbidities, and is equally familial; however, girls have a shorter duration of mania, more depressive episodes, and are more at risk for comorbid panic disorder and substance use disorders [48]. Girls, compared to boys with BD, less commonly have co-occurring disruptive behavioral disorders such as ADHD and have less prominent behavioral problems before puberty, whereas after puberty, the gender distribution appears more equal and hypersexuality may be more common [49]. These gender differences may influence trends in the diagnosis of DMDD, which may more commonly manifest in boys than girls, and, by definition, is diagnosed prepubertally.

Distinguishing Pediatric Bipolar I Disorder From Typical Behavior and Other Psychiatric Disorders In this section, we discuss how the symptoms and, when available, the neurobiology of BD-I can be distinguished from typical development and from other mood and psychiatric disorders. To distinguish BD from typical behavior, symptoms must persist, cause social, academic, or family impairment, and represent a significant change from the child’s baseline. Functional impairments provide important early clues about escalating and unremitting behaviors that warrant clinical attention. Symptoms like grandiosity and elation must be inappropriate to the context in which they occur [50], and pathological elation, decreased need for sleep, and hypersexuality are relatively specific to BD [38, 50]. Irritability can create diagnostic challenges, as it is also a diagnostic criterion for pediatric major depressive episodes and generalized anxiety disorder and is common in pervasive developmental disorders, CD, ADHD, substance use disorders, obsessivecompulsive disorder, and is central to the new diagnosis of DMDD. Irritability as a symptom of BD must be episodic and occur alongside at least four additional symptoms of mania [50]. Irritability also has different trajectories in youth, depending on whether or not it is accompanied by euphoria [51]. In a cohort of 309 youth with either BD-I, BD-II, or bipolar disorder specified other or unspecified other, youth who experienced irritability without elation had a similar risk for mania but an increased risk for depression compared with

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elated-only youth and youth with irritability + elation during a 4-year follow-up [51].

Other Specified and Unspecified Bipolar and Related Disorder (Formerly Bipolar Disorder Not Otherwise Specified)

Bipolar II Disorder (BD-II)

Bipolar disorder not otherwise specified (BD-NOS), which is now referred to as bipolar disorder specified other and unspecified bipolar and related disorder in DSM-5, is used for youth who have symptoms that are outside their normal range of behavior but do not meet full criteria for BD-I, BD-II, or cyclothymic disorder [34]. It is difficult to differentiate between bipolar disorder specified other or unspecified other and cyclothymic disorder using DSM criteria [58]; however, cyclothymic disorder criteria are specific, while bipolar disorder specified other or unspecified other criteria intentionally lack specificity in order to capture problems that fall outside of defined BD subtypes [68]. In both disorders, symptoms do not meet full criteria for mania or major depression, but cyclothymic disorder requires 1 year in youth (2 years in adults) of chronic hypomanic and depressive symptoms, while bipolar disorder specified other or unspecified other commonly includes problems with symptoms of hypomania and/or depression that do not meet duration criteria for BD-I, BD-II, or cyclothymic disorder [68]. The Course and Outcome of Bipolar Youth (COBY) study defined DSM-IV BD-NOS as a discrete period of expansive, irritable, or elevated mood that does not meet BD-I or BD-II criteria and is a significant departure from baseline functioning, with two associated manic symptoms (three if the mood is only irritable) [69]. In addition, symptoms must be present for at least 4 consecutive or nonconsecutive days over the lifetime, with at least 4 h of symptoms per day. The COBY study found that BD-NOS and BD-I youth were similar in age of onset, illness and comorbid disorders duration, rate of lifetime history of suicidal ideation, family history, and types of manic symptoms [69]. However, youth with BD-I exhibited more severe manic symptoms, more functional impairment, more hospitalizations, a higher likelihood of attempting suicide, and a higher rate of psychosis. In a study of 707 children aged 6–12 years, youth with BD-NOS had less severe prior functional impairment than that of youth with BD-I, but the two groups showed similar levels of current symptom severity and functional impairment relative to youth without a bipolar diagnosis [70]. Youth with BD-NOS and BD-I were also similar in rates of elated mood and parental psychiatric history, and both groups were more likely to have a parental history of mania than that of youth without a bipolar spectrum diagnosis. In the Pittsburgh Bipolar Offspring study, offspring of parents with BD were more likely to have BDNOS than BD-I and were 13 times more likely to meet BDNOS criteria than that of controls [71]. Bipolar disorder specified other or unspecified other may commonly represent a prodromal form of BD-I, although some youth with bipolar disorder specified other or

BD-II is diagnosed in individuals with a history of at least one hypomanic episode and one major depressive episode and without a history of manic episodes [34]. Youth with BD are generally more at risk for executive function [52] and cognitive deficits [53–55] than that of controls. Importantly, one recent study suggests that BD-I youth may have more severe cognitive impairment than that of BD-II youth [56•], performing more poorly on attention, executive function, working memory, visual memory, verbal learning, and memory domains than that of healthy controls and more poorly than that of BD-II youth on all domains except for working memory. BD-II patients performed more poorly than that of healthy controls on memory and verbal learning. These findings require replication and further investigation to determine if they represent cognitive endophenotypes of pediatric BD.

Cyclothymic Disorder Cyclothymic disorder is a mild form of BD characterized by at least 1 year of numerous periods of hypomanic and depressive symptoms that do not meet full criteria for a major depressive or hypomanic episode [34]. Family history of mental illness is pervasive among youth with cyclothymic disorder [57, 58], and familial rates of BD-I are similar between those with cyclothymic disorder and BD-I [59, 60]. Cyclothymic disorder may be a prodrome for the development of BD-I or II [61]. Two validation studies concluded that cyclothymic disorder falls on the bipolar spectrum and can be reliably differentiated from other nonbipolar childhood disorders [57, 58, 62]. In both studies, youth with cyclothymic disorder experienced significantly more irritability and higher levels of sleep disturbance than that of nonbipolar youth. The average age of onset was 6 years, and three fourths had an onset before age 10, which is significantly earlier than those with BD-II or depression [57]. Cyclothymic disorder may be associated with as much impairment as BD-I and II [44, 63]. Children’s Global Assessment scores were similar between youth with cyclothymic disorder and other bipolar spectrum disorders [57, 58, 62]. However, youth with cyclothymic disorder tend to experience sustained symptom fluctuation [64] while those with BD-I or II tend to achieve remission more quickly and experience symptom-free periods [44, 65]. The chronic nature of cyclothymic disorder often indicates a treatment-resistant form of mood disorder [44, 65] that is associated with higher levels of comorbidity [66, 67].

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unspecified other may not worsen over time and may even improve [45•]. In the COBY study, 38.3 % of youth with BDNOS developed BD-I or II over a 4-year period [44]. Axelson et al. found that 45 % of 140 youth with BD-NOS experienced conversion to BD-I or II at a 5-year follow-up [7]. The strongest baseline predictor of conversion was first- or second-degree family history of hypomania or mania. Differential patterns of abnormal neural functioning during emotion processing and regulation have distinguished youth with bipolar disorder specified other or unspecified other from youth with BD-I [72]. In the first study, to investigate neural differences across the bipolar spectrum in youth, 18 youth with BD-I, 16 youth with DSM-IV BD-NOS, and 18 healthy controls performed two emotional face-labeling tasks while undergoing functional MRI (fMRI). Compared with controls, youth with BD-I showed greater amygdala, ventromedial prefrontal cortex (VMPFC), and dorsolateral prefrontal cortex (DLPFC) activity while labeling happy faces and decreased DLPFC activity in response to fearful faces, whereas youth with BD-NOS had reduced VMPFC and DLPFC activity while labeling neutral faces. Youth with BD-NOS showed reduced amygdala, VMPFC, and DLPFC activity while labeling neutral faces compared to that of youth with BD-I. The neural specificity of pediatric bipolar spectrum disorders demonstrated by this study warrants replication to advance our understanding of the pathophysiology of bipolar disorders in youth. Major Depressive Disorder (MDD) and Persistent Depressive Disorder Depression is often the first symptom of pediatric BD, and by adulthood, 20 % of youth with MDD experience manic episodes [73]. In a sample of 52 youth with BD-I, prodromal depressed mood was reported in 53.8 % [31•]. A family history of BD, rapid onset of MDD, psychotic features, and psychomotor retardation predict the development of mania in youth with MDD [74]. In DSM-5, the specifier “with mixed features” has been added to the major depressive episode (MDE) criteria and describes a depressive episode that involves at least three opposite pole (i.e., excluding irritability, distractibility, and psychomotor agitation) mood elevation symptoms. MDEs with mixed features (also known as mixed depression) may occur not only in BD but also in individuals who have never met full criteria for a hypomanic or manic episode (i.e., in MDD). Psychotic MDD is a severe subtype that rarely onsets before adolescence and commonly develops into BD in patients less than 30 years of age [74]. Persistent depressive disorder is a new diagnosis in the DSM-5 that includes chronic MDD and the former DSM-IV diagnosis of dysthymic disorder [34]. Pediatric bipolar depression is associated with significant impairment [75•] including social withdrawal, changes in

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appetite, sensitivity to rejection, high levels of guilt, and suicidality [76], and in view of its pervasiveness, over time may be even more detrimental to youths’ functioning than that of mania [75•]. Distinguishing between unipolar and bipolar depression can be difficult (MDD is the most common initial misdiagnosis in individuals with BD [77, 78]), as their DSM-5 MDE criteria do not differ and MDD is also generally an episodic disorder [50]. Indeed, the presence of manic or hypomanic episodes is the defining feature of BD in contrast to MDD [50]. Other qualitative differences between unipolar and bipolar depression include atypical symptoms like psychomotor changes and mood lability [79]. Youth with bipolar depression have more hopelessness, anhedonia, comorbid disorders, hospitalizations, more severe depressive episodes, an earlier age of onset, more depressive episodes, and lower functioning than those with unipolar depression [15, 80]. The presence of multiple risk factors, such as early onset of depression (prior to age 25 years), atypical depressive features (hyperphagia, hypersomnia, anergy), antidepressant “misadventures” (inefficacy or mood destabilization), having a firstdegree relative with BD, and having a personal history of psychosis and/or highly recurrent depression, increases the risk of a bipolar outcome in individuals presenting with depression [81]. Recent studies have found that differential neural patterns may distinguish youth with bipolar depression from youth with unipolar depression. During the NoGo condition in the Go/NoGo task, adolescents with bipolar depression (BD-I and BD-II), but not unipolar depression, were found to have increased left anterior cingulate cortex (ACC) activity compared to that of healthy controls [82]. During the Go condition, adolescents with unipolar depression, but not bipolar depression, were found to exhibit increased left caudate activity. Increased reaction time was positively correlated with DLPFC activation in adolescents with unipolar, but not bipolar, depression. In addition, adolescents with BD-I or II depression were found to exhibit significantly lower activity in the insula and temporal cortex in response to happy faces and lower activity in the frontal precentral cortex in response to fearful faces, relative to youth with unipolar depression [83]. Further studies investigating these neural differences may clarify the common and distinct underlying pathophysiologies of bipolar and unipolar depression. Disruptive Mood Dysregulation Disorder (DMDD) DMDD prevalence rates are estimated to be 3.3 % in a preschool sample and 0.8–1.1 % in older youth [84•]. These rates decreased slightly when exclusion criteria were strictly applied. DMDD was comorbid with another psychiatric disorder 62 to 92 % of the time. Evidence suggests that chronic irritability is associated with future unipolar mood disorders, rather than bipolar mood disorders [35, 85–87].

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DMDD may have distinguishing neural features. One fMRI study examined the neural responses to frustration in 23 healthy children and 19 children (ages 8–17) with chronic irritability, all of whom may meet criteria for DMDD [88]. During the frustration condition, in response to negative feedback, children with chronic irritability exhibited reduced activation of the left amygdala, the left and right striatum, the parietal cortex, and the posterior cingulate compared to healthy children, which are regions associated with emotion, attention, and reward processing. Further evaluation of the distinct neural features of DMDD is needed. DMDD and BD cannot coexist. BD involves distinct manic and major depressive episodes, with or without temper outbursts, while DMDD is characterized by severe chronic and episodic irritability and requires temper outbursts in order to meet diagnostic criteria. In addition, BD diagnosis is not limited to a specific age range, and it has a peak onset during late adolescence and early adulthood, while DMDD is only diagnosed between ages 6 and 18 and must onset before age 10. Unlike BD, DMDD can be accompanied by MDD but cannot be associated with psychosis or ODD. A diagnosis of DMDD takes precedence when a child meets criteria for both DMDD and ODD. ADHD and Other Disruptive Behavioral Disorders (ODD, Conduct Disorder) In a meta-analysis, ADHD was the most common comorbidity with pediatric BD (62 %), followed by ODD (53 %) and CD (19 %) [89]. These disorders have several overlapping symptoms with BD. For example, youth with ADHD and youth with BD can both present with hyperactivity, impulsivity, low frustration tolerance, distractibility, and increased talkativeness [90•]. BD may be indicated if overlapping symptoms intensify during a mood episode [50]. When distinguishing BD from disruptive disorders, it is important to determine that the mood episode symptoms and behavior represent a significant departure from baseline functioning [35]. The primary distinguishing features of BD are its episodic nature and distinct symptoms of mania [38]. For example, in contrast to the reduced need for sleep seen in pediatric BD, youth with ADHD may have insomnia but their need for sleep is unchanged [50]. Youth with ODD may defy bedtime rules, but sleep disturbance is not a common characteristic. Mood-related grandiosity and hypersexuality are also distinctly characteristics of BD—grandiosity and hypersexuality are not symptomatic of ADHD—and youth with ODD often defy authority, but this is not necessarily mood-related [50]. Recent research has identified other potential distinctions between youth with ADHD and youth with BD. Children with ADHD have higher rates of comorbidities with other disruptive behavioral, psychotic, anxiety, or pervasive

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developmental disorders than do children with BD; however, those with BD are four times more likely to be hospitalized [91]. Youth with BD (current manic or hypomanic episode) were found to exhibit more reactive and verbal aggression and to report more depressive symptoms than that of youth with ADHD [92]. In addition, in a study on family functioning deficits, youth with BD-I exhibited problem-solving impairment compared to controls, while youth with ADHD did not [93]. It is of note, however, that (as is common clinically) 70 % of the BD-I sample in this study had a comorbid diagnosis of ADHD. In contrast to other differential diagnoses for BD, there are several studies that have examined the neurobiological distinctions between ADHD and BD. Youth with ADHD may also have more severe executive function deficits than that of youth with bipolar spectrum disorders [94]. In addition, youth with BD and a history of psychotic symptoms may inefficiently encode verbal material, while youth with ADHD may have memory problems characterized by problems with free recall [95]. Youth with BD and BD + ADHD also exhibited increased intraindividual variability in reaction time, more sluggish motor preparedness, and slower processing speed than that of youth with ADHD [96]. Youth with BD-I and ADHD may also have differing alterations in emotional face identification [90•]. Pediatric BD-I patients made significantly more identification errors on child happy faces and were more likely to make errors on low-intensity child happy faces than that of ADHD youth, indicating that youth with BD-I may have specific abnormalities in identifying happy faces. In addition, BD-I youth made significantly more errors on child angry faces than that of controls, and ADHD youth made significantly more errors on child fearful faces than that of controls. Finally, differences in brain structure and function may distinguish the two disorders. ADHD has been associated with decreased caudate and putamen volumes, while pediatric BD has been associated with increased caudate, putamen, and globus pallidus volumes [97]. Furthermore, whereas BD may be characterized by an “emotionally-driven” impulsivity associated with a reward/affect system or ventral frontostriatal circuitry, ADHD may be characterized by a “cognitivelydriven” impulsivity associated with the behavior regulation system or dorsal frontostriatal circuitry [98].

Anxiety Disorders An analysis from the Integrated Healthcare Information Services cohort found that 51 % of youth with BD also met criteria for at least one co-occurring anxiety disorder, commonly generalized anxiety disorder (GAD) and separation anxiety disorder [99]. Familial rates and clinical features of BD have been found to be similar in youth with BD-I with and

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without post-traumatic stress disorder (PTSD), suggesting that youth can be affected by both disorders [100]. Symptom overlap between traumatized youth and BD-I includes hyperarousal and emotional dysregulation [100], and youth with GAD and BD can both present with overlapping symptoms such as irritability and sleep disturbance. However, in contrast to the episodic nature of BD, youth with generalized anxiety generally have chronic symptoms, such as chronic irritability, restlessness, and impaired concentration [50]. To count toward a diagnosis of BD, such symptoms must be heightened during a mood episode [50]. Psychotic Disorders and Autism Spectrum Disorders Differentiating between pediatric schizophrenia and BD can be challenging, particularly when psychotic symptoms are present [101]. When psychotic and mood symptoms cooccur but the individual experiences a 2-week or longer period of psychosis without significant mood symptoms, schizoaffective disorder or schizophrenia diagnoses should be considered [102]. If psychotic symptoms occur only within a mood episode, the diagnosis is mood disorder with psychotic features. The DSM-5 aimed to shift schizoaffective disorder from a cross-sectional to a longitudinal diagnosis that takes the entire time period from the psychosis onset until the current episode into account rather than delimiting a single episode and is diagnosed only if full mood episodes are present for the majority of the illness [102]. Youth with BD more commonly have mood-congruent delusions and less commonly have hallucinations and loosening of associations than that of youth with schizophrenia [101] and milder but similar cognitive deficits are observed in pediatric BD and pediatric schizophrenia, including deficits in verbal learning and memory, processing speed, and executive control [103]. Furthermore, in one prospective study, youth with schizophrenia demonstrated poorer insight than those with BD at 6- and 12-month followup, but not at baseline [104]. Thus, the progressive nature of these disorders in youth may differ. Autism spectrum disorders (ASD) now encompass the previous diagnoses of pervasive developmental disorders, Asperger’s syndrome, and autism [34]. In contrast to BD which is more commonly initially diagnosed in adolescence, ASD is typically diagnosed in the initial 2–3 years of life. Both BD and ASD may demonstrate deficits in socialemotional reciprocity, but ASD is more commonly characterized by developmental delays as well as impairments in social functioning, verbal and nonverbal communication, and stereotyped or repetitive body movements, speech, or use of objects; hyper- or hyporeactivity to sensory stimuli; highly restricted or fixated interest; and inflexible adherence to routines, sameness, or ritualized patterns. In a study of 155 youth with BD-I, 30 % met DSM-III-R criteria for ASD. Those with ASD comorbidity had significantly earlier age of onset of BD-

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I but similar phenotypic and familial correlates as BD-I youth [105]. There may be neurobiological differences that can help to distinguish the two disorders, as youth with BD-I and II have been found to have a significantly smaller left anterior cingulate gyrus (ACG) than that of youth with ASD [106]. Substance Use Disorders Twelve percent of youth with BD have a comorbid substance use disorder [89]. A thorough assessment of the temporal course of symptoms and substance use is crucial in order to differentiate bipolar mania from substance-induced manic symptoms, as intoxication or withdrawal can precipitate manic symptoms, and the risk-taking behaviors associated with mania can increase substance use [50]. Urine drug screening can also improve diagnostic accuracy [107] as can observation during extended periods of abstinence from substance use. Borderline Personality Traits Borderline personality traits, such as emotional liability, anxiousness, separation insecurity, depressivity, impulsivity, risktaking, and hostility, do not remit in a sustained fashion, are consistent between situations, and are developmentally and culturally inappropriate. In contrast to borderline personality disorder, BD is characterized by highly episodic severe mood symptoms and psychomotor disturbances that are not seen during periods of sustained remission and typically a family history of BD [108].

Conclusion Accurate identification of pediatric BD continues to be a significant challenge. Unique presentations in youth and overlapping symptoms with other psychiatric disorders complicate diagnosis, which can lead to misdiagnosis, inappropriate treatment, and delay of appropriate interventions. Though the field has made significant advances in distinguishing BD from other childhood psychiatric disorders, research remains challenged by high rates of comorbidity, confounding effects of medication exposure, retrospective and cross-sectional data, selection bias, and limitations of biomarkers. In addition, the continuity of BD from childhood through adulthood must be determined with longitudinal studies, and controversies surrounding BD need to be resolved, such as its phenomenology in very young children and the diagnostic validity of DMDD. Finally, more research is needed to improve our understanding of the neurobiological and genetic underpinnings of BD, which will allow clinicians to more accurately identify atrisk youth and provide early interventions.

516, Page 8 of 11 Compliance with Ethics Guidelines Conflict of Interest Manpreet K. Singh declares no conflict of interest. Dr. Singh receives research support from Stanford Child Health Research Institute. Kiki D. Chang receives research support from the National Institute of Mental Health and Stanford University. Dr. Chang is also an unpaid consultant for GlaxoSmithKline, Eli Lilly, and Bristol-Myers Squibb. He is on the Data Safety Monitoring Board for Sunovion. In the past two years, he has received research support from GlaxoSmithKline and Merck. 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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