In less than a 10-year period in the United States, youth outpatient visits associated with a bipolar disorder (BD) diagnosis increased more than 40-fold.1 High rates of PBD are not seen in other countries, including the United Kingdom, Germany, Spain, Denmark, Finland, Brazil, Turkey, and India.2 Moreover, psychotropic medications are prescribed at much higher rates in the US than in other countries.3
BD has long been defined as a mood disorder consisting of episodes of mania and depression, separated by periods of more moderate mood, known as euthymia (Table 1). In the 1990s, some researchers hypothesized that BD might present differently in youth compared to adults.4–6 They suggested that irritability could be a youth equivalent of euphoria, and instead of distinct episodes of mood symptoms, youth might present with severe and chronic nonepisodic irritability or “ultra-rapid cycling.” These hypotheses led to modified pediatric bipolar disorder (PBD) criteria, which contributed significantly to the increased rates of PBD diagnoses in the US. Additional controversy concerns age of onset for PBD. It has long been accepted that BD usually presents from adolescence to early adulthood, and prepubescent mania is rare. However, researchers using modified PBD criteria reported mean onset of youth “bipolar” symptoms in preschool or early elementary school.4 Subsequent longitudinal studies found that youth with chronic nonepisodic irritability rarely develop BD; instead they most often present later in life with unipolar depression (depression without mania), anxiety disorders, and disruptive behavior.7–11 As a result, the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5)12 emphasizes that mania must be both episodic and a clear change from baseline.
Definition of Terms Relating to Bipolar Disorder
Creation of a New Diagnosis: Disruptive Mood Dysregulation Disorder
Concern regarding inappropriate PBD diagnoses led to the creation of a new diagnosis in DSM-5,12 disruptive mood dysregulation disorder (DMDD), to be the “diagnostic home” for severe nonepisodic irritability. The proposed inclusion of a DMDD prototype in DSM-512 was controversial because there was insufficient evidence to support DMDD as a distinct diagnosis, research on severe mood dysregulation (SMD, on which DMDD was based) was limited, and SMD research came primarily from a single research group. Furthermore, DMDD is based on SMD, but SMD and DMDD diagnostic criteria, although similar, are not identical, so the limited research on SMD could not be generalized to DMDD. When it was proposed as a diagnosis, there was no research on DMDD.13
Most current DMDD research involves SMD and/or modified DMDD criteria applied retrospectively. These studies7–9,14,15 have found that DMDD is associated with low family income, is not stable as a diagnosis, seldom occurs as a sole diagnosis, is often comorbid with other conditions, and is not clearly differentiated from oppositional defiant disorder (ODD) or conduct disorder. In addition, youth presenting for treatment with disruptive behavior, anxiety, and mood disorders will frequently meet criteria for DMDD.7–9,14,15 In DSM-512 field trials, DMDD had limited diagnostic reliability. Given current research findings, some question the diagnostic validity and utility of DMDD and whether inclusion in DSM-512 was premature. Furthermore, the World Health Organization and International Statistical Classification of Diseases and Related Health Problems, 11th edition (ICD-11) Working Group on the Classification of Mental and Behavioural Disorders in Children and Adolescents rejected a version of DMDD for ICD-11.16
Differential Diagnosis of Bipolar Disorder
Table 2 shows the criteria used in the differential diagnosis of BD. When making the diagnosis, it is important to know how BD relates to attention-deficit/hyperactivity disorder (ADHD), ODD, and DMDD.
Differential Diagnosis of Bipolar Disorder
The American Academy of Child and Adolescent Psychiatry practice parameter for the Assessment and Treatment of Children and Adolescents with Bipolar Disorder recommends a comprehensive, multimodal approach combining psychopharmacological and psychosocial therapies.17 Polypharmacy and complex medication regimens are common in PBD. Varying entry criteria among different studies complicate research findings, and more long-term effectiveness and safety studies are needed.
Second-generation antipsychotics (SGAs) and “mood stabilizers” (MSs) are the most studied and prescribed medications for PBD. In this article, MSs refers to lithium and anticonvulsants such as divalproex, carbamazepine, oxcarbazepine, and lamotrigine.The SGAs include risperidone, quetiapine, aripiprazole, ziprasidone, and olanzapine. Some classifications include SGAs as MSs because SGAs have mood-stabilizing properties. This article distinguishes SGAs from MSs because SGAs differ from MSs in adverse effects and PBD efficacy.
Current PBD research finds SGAs more efficacious than MSs and placebo. In randomized controlled trials (RCTs) of 3 to 4 weeks, aripiprazole,18 risperidone,19 quetiapine,20 and olanzapine21 were more effective than placebo for youth acute mania. Aripiprazole was superior to placebo for mania in a 6-week RCT for youth with PBD and ADHD.22 Open-label studies report lithium, divalproex, carbamazepine, oxcarbazepine, and lamotrigine are effective for PBD.23 One 8-week RCT found lithium more effective than placebo for manic symptoms.24 However, in other RCTs,23 lithium, divalproex, and oxcarbazepine did not differentiate from placebo, and carbamazepine and lamotrigine have not been studied in RCTs. Head-to-head RCTs for PBD find quetiapine more effective than divalproex,25 risperidone superior to divalproex,26 and risperidone more effective than lithium or divalproex.27 In co-occurring ADHD and PBD, after first treating mood symptoms to euthymia with medications, one can prescribe ADHD medications without significantly increasing risk for mood destabilization.28
SGAs and MSs can cause significant adverse effects, and youth are more sensitive than adults to these effects. Youth on SGAs and MSs require ongoing monitoring. The Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in Children29 developed SGA monitoring guidelines. Although not specific to youth, the International Society for Bipolar Disorders developed bipolar treatment (SGA and MS) safety monitoring guidelines.30 Readers are referred to BD treatment and monitoring resources for more information.23,29–31
SGAs are commonly associated with sedation, weight gain, extrapyramidal side effects, dizziness, and dry mouth. SGAs can also cause dyslipidemias, glucose dysregulation, metabolic syndrome, hyperprolactinemia, akathisia, agitation, tremors, nausea, gastrointestinal symptoms, sexual side effects, and headache. Rare but potentially serious adverse effects include tardive dyskinesia, neuroleptic malignant syndrome, lowered blood cell counts, elevated liver enzymes, QTC lengthening, and suicidal ideation. Individual SGAs differ to some degree in their adverse effects.29,30
The adverse effects of MSs are more heterogeneous than SGAs. Various MSs are associated with weight gain, sedation, dyslipidemias, dizziness, nausea, gastrointestinal symptoms, headache, tremor, and visual problems. Some MSs can cause hepatic, pancreatic, renal, dermatologic, and bone marrow effects, and, rarely, severe reactions in these systems. Divalproex can cause polycystic ovaries, lithium will affect thyroid and to a lesser extent renal functioning, and both, along with carbamazepine, are associated with congenital malformations. Lithium has a narrow therapeutic window.29,30
A review of PBD psychosocial treatments identified a number of interventions with some level of empirical support.32 No intervention met the highest level of empirical support, but the review identified some promising interventions.32 The specific treatments are not widely available, but share some “common elements.” Promising interventions (1) typically involve family members and provide psychoeducation to youth and family on the nature of bipolar disorder—including symptoms, etiology, course, effective treatment, and risks for relapse; (2) stress the importance of taking medications as prescribed and provide methods for promoting medication adherence; and (3) support symptom management. The treatments also use practices that are not BD-specific and are beneficial for a wide range of emotional and behavioral disorders, including establishing good communication among family members; teaching problem-solving, social, and emotion regulation skills; and using cognitive-behavioral therapy (CBT) techniques. Primary care providers should refer youth with PBD to behavioral health providers employing these treatment elements. Clinicians should also address academic and vocational functioning, and collaborate with any additional systems youth are involved with, such as child welfare or juvenile justice.
Treatment of DMDD
Youth diagnosed with DMDD have high levels of behavioral health needs. Research on DMDD-specific psychotropic or psychosocial treatments is limited. Psychopharmacologic strategies are only one part of a treatment plan and should include identifying and treating comorbid medication-responsive conditions, such as ADHD. Given the overlap of DMDD with disruptive behavior disorders, promising psychosocial treatments include those effective for youth disruptive behavior (such as parent management training), youth skills training, CBT, and intensive family-based treatments.
Potential Roles for Primary Care Providers
PBD and DMDD are long-term conditions with significant risk for negative functional outcomes. Primary care providers (PCPs) will not usually have the time or background to assess and diagnose PBD or provide formal psychosocial interventions, but PCPs can play important roles. PCPs are central in coordinating and collaborating care with youth, families, educators, and behavioral and other health care providers. Providing psychoeducation will facilitate youth and family engagement in assessment and treatment. Knowing the common elements of promising psychosocial interventions will inform behavioral health care referrals. Youth diagnosed with PBD are sometimes prescribed complex medication regimens. PCPs should prescribe, maintain, and/or adjust medications according to their experience and comfort level, and seek consultation when appropriate. Youth receiving medications will require ongoing monitoring, including height/weight, vital signs, laboratory tests, and positive and negative effects.29,30 PCPs can help families navigate the behavioral health system; develop and articulate treatment goals, questions, and concerns; and assess progress on behavioral, emotional, and functional goals.
The marked increases of BD diagnoses and psychotropic prescriptions to US youth are a source of controversy. Controversies aside, youth diagnosed with BD or DMDD, or presenting with severe irritability often require high levels of behavioral health care.
PBD is a mood disorder with periods of mania and depression that are episodic and a change from baseline. Youth with PBD should be treated with a combination of psychosocial and psychiatric treatments, and these interventions should be coordinated. Clinicians should refer to psychosocial interventions that involve family members and provide psychoeducation to youth and family about BD (symptoms, etiology, course, effective treatment, risks for relapse, and protective factors), and how to promote medication adherence and manage symptoms. PCPs should also refer youth with BD to behavioral health providers who emphasize good communication and positive interactions among family members, teach skills (problem-solving, social, and emotion regulation), and use CBT techniques. Short-term studies to date find SGAs to be more effective than MSs.
PCPs should coordinate and collaborate with behavioral health providers and other stakeholders. PCPs can help youth and families develop and advocate for behaviorally specific and long-term functional goals, and navigate behavioral health, education, and other youth-serving systems. Youth receiving psychiatric medications to treat PBD require ongoing monitoring.
- Moreno C, Laje G, Blanco C, Jiang H, Schmidt AB, Olfson M. National trends in the outpatient diagnosis and treatment of bipolar disorder in youth. Arch Gen Psychiatry. 2007;64(9):1032–1039. doi:10.1001/archpsyc.64.9.1032 [CrossRef]
- Soutullo CA, Chang KD, Díez-Suárez A, et al. Bipolar disorder in children and adolescents: international perspective on epidemiology and phenomenology. Bipolar Disord. 2005;7(6):497–506. doi:10.1111/j.1399-5618.2005.00262.x [CrossRef]
- Steinhausen HC. Recent international trends in psychotropic medication prescriptions for children and adolescents. Eur Child Adolesc Psychiatry. 2015;24(6):635–640. doi:10.1007/s00787-014-0631-y [CrossRef]
- Parens E, Johnston J. Controversies concerning the diagnosis and treatment of bipolar disorder in children. Child Adolesc Psychiatry Ment Health. 2010;4:9. doi:10.1186/1753-2000-4-9 [CrossRef]
- Geller B, Zimerman B, Williams M, et al. Diagnostic characteristics of 93 cases of a prepubertal and early adolescent bipolar disorder phenotype by gender, puberty and comorbid attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol. 2000;10(3):157–164. doi:10.1089/10445460050167269 [CrossRef]
- Wozniak J, Biederman J, Kiely K, et al. Mania-like symptoms suggestive of childhood-onset bipolar disorder in clinically referred children. J Am Acad Child Adolesc Psychiatry. 1995;34(7):867–876. doi:10.1097/00004583-199507000-00010 [CrossRef]
- Axelson D, Findling RL, Fristad MA, et al. Examining the proposed disruptive mood dysregulation disorder diagnosis in children in the Longitudinal Assessment of Manic Symptoms study. J Clin Psychiatry. 2012;73(10):1342–1350. doi:10.4088/JCP.12m07674 [CrossRef]
- Brotman MA, Schmajuk M, Rich BA, et al. Prevalence, clinical correlates, and longitudinal course of severe mood dysregulation in children. Biol Psychiatry. 2006;60(9):991–997. doi:10.1016/j.biopsych.2006.08.042 [CrossRef]
- Copeland WE, Shanahan L, Egger H, Angold A, Costello EJ. Adult diagnostic and functional outcomes of DSM-5 disruptive mood dysregulation disorder. Am J Psychiatry. 2014;171(6):668–674. doi:10.1176/appi.ajp.2014.13091213 [CrossRef]
- Deveney CM, Hommer RE, Reeves E, et al. A prospective study of severe irritability in youths: 2- and 4-year follow-up. Depress Anxiety. 2015;32(5):364–372. doi:10.1002/da.22336 [CrossRef]
- Stringaris A, Cohen P, Pine DS, Leibenluft E. Adult outcomes of youth irritability: a 20-year prospective community-based study. Am J Psychiatry. 2009;166(9):1048–1054. doi:10.1176/appi.ajp.2009.08121849 [CrossRef]
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.
- Axelson DA, Birmaher B, Findling RL, et al. Concerns regarding the inclusion of temper dysregulation disorder with dysphoria in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition. J Clin Psychiatry. 2011;72(9):1257–1262. doi:10.4088/JCP.10com06220 [CrossRef]
- Dougherty LR, Smith VC, Bufferd SJ, et al. DSM-5 disruptive mood dysregulation disorder: correlates and predictors in young children. Psychol Med. 2014;44(11):2339–2350. doi:10.1017/S0033291713003115 [CrossRef]
- Mayes SD, Mathiowetz C, Kokotovich C, et al. Stability of disruptive mood dysregulation disorder symptoms (irritable-angry mood and temper outbursts) throughout childhood and adolescence in a general population sample. J Abnorm Child Psychol. 2015;43(8):1543–1549. doi:10.1007/s10802-015-0033-8 [CrossRef]
- Lochman JE, Evans SC, Burke JD, et al. An empirically based alternative to DSM-5's disruptive mood dysregulation disorder for ICD-11. World Psychiatry. 2015;14(1):30–33. doi:10.1002/wps.20176 [CrossRef]
- McClellan J, Kowatch R, Findling RLWork Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(1):107–125. doi:10.1097/01.chi.0000242240.69678.c4 [CrossRef]
- Findling RL, Nyilas M, Forbes RA, et al. Acute treatment of pediatric bipolar I disorder, manic or mixed episode, with aripiprazole: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2009;70(10):1441–1451. doi:10.4088/JCP.09m05164yel [CrossRef]
- Haas M, Delbello MP, Pandina G, et al. Risperidone for the treatment of acute mania in children and adolescents with bipolar disorder: a randomized, double-blind, placebo-controlled study. Bipolar Disord. 2009;11(7):687–700. doi:10.1111/j.1399-5618.2009.00750.x [CrossRef]
- Pathak S, Findling RL, Earley WR, et al. Efficacy and safety of quetiapine in children and adolescents with mania associated with bipolar I disorder: a 3-week, double-blind, placebo-controlled trial. J Clin Psychiatry. 2013;74(1):e100–109. doi:10.4088/JCP.11m07424 [CrossRef]
- Tohen M, Kryzhanovskaya L, Carlson G, et al. Olanzapine versus placebo in the treatment of adolescents with bipolar mania. Am J Psychiatry. 2007;164(10):1547–1556. doi:10.1176/appi.ajp.2007.06111932 [CrossRef]
- Tramontina S, Zeni CP, Ketzer CR, Pheula GF, Narvaez J, Rohde LA. Aripiprazole in children and adolescents with bipolar disorder comorbid with attention-deficit/hyperactivity disorder: a pilot randomized clinical trial. J Clin Psychiatry. 2009;70(5):756–764. doi:10.4088/JCP.08m04726 [CrossRef]
- Liu HY, Potter MP, Woodworth KY, et al. Pharmacologic treatments for pediatric bipolar disorder: a review and meta-analysis. J Am Acad Child Adolesc Psychiatry. 2011;50(8):749–762.e39. doi:10.1016/j.jaac.2011.05.011 [CrossRef]
- Findling RL, Robb A, McNamara NK, et al. Lithium in the acute treatment of bipolar i disorder: a double-blind, placebo-controlled study. Pediatrics. 2015;136(5):885–894. doi:10.1542/peds.2015-0743 [CrossRef]
- DelBello MP, Kowatch RA, Adler CM, et al. A double-blind randomized pilot study comparing quetiapine and divalproex for adolescent mania. J Am Acad Child Adolesc Psychiatry. 2006;45(3):305–313. doi:10.1097/01.chi.0000194567.63289.97 [CrossRef]
- Pavuluri MN, Henry DB, Findling RL, et al. Double-blind randomized trial of risperidone versus divalproex in pediatric bipolar disorder. Bipolar Disord. 2010;12(6):593–605. doi:10.1111/j.1399-5618.2010.00850.x [CrossRef]
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Definition of Terms Relating to Bipolar Disordera
||DSM-512 defines a manic episode as “A distinct period of abnormally and persistently elevated, expansive, or irritable mood, and abnormally and persistently increased goal-directed activity or energy, lasting at least 1 week and present most of the day, nearly every day (or any duration if hospitalization is necessary).” Manic symptoms include inflated self-esteem or grandiosity, decreased need for sleep, rapid pressured speech, flight of ideas, racing thoughts, or excessive involvement in activities that have a high potential for painful consequences
||A hypomanic episode is similar to a manic episode, except the episode is not severe enough to cause a marked impairment in social or occupational functioning. Mood and functional disturbances are observable to others, and minimum duration of symptoms is 4 days
||To be diagnosed with BD, a person must have experienced a manic or hypomanic episode. People who have experienced a manic episode are diagnosed with BD I, and people who have experienced a hypomanic episode are diagnosed with BD II. BDis also known as manic-depressive illness
|Pediatric bipolar disorder
||This article uses the term pediatric bipolar disorder to refer to BD in youth. BD is a DSM diagnosis whereas PBD is not. Use of the term PBD became more widespread when some clinicians and researchers proposed youth BD might present differently than in adults33
|Severe mood dysregulation
||A clinical syndrome developed by a group of researchers at NIMH to study youth with severe and chronic irritability. SMD is not a DSM diagnosis
|Disruptive mood dysregulation disorder
||This diagnosis first appeared in DSM-512 and is based on SMD. DMDD and SMD diagnostic criteria are similar, but not identical. DMDD is characterized by severe, recurrent temper outbursts that are inconsistent with developmental level, and occur on average at least 3 times per week. The mood between temper outbursts is persistently irritable and angry
Differential Diagnosis of Bipolar Disorder
||How To Differentiate BD from ADHD, ODD, and DMDD
||Studies of PBD and ADHD find high levels of comorbidity (22%–98%).28 Overlapping symptoms, such as impulsivity, irritability, talkativeness, increased motor activity, and poor sleep, complicate distinguishing PBD from ADHD. However, ADHD symptoms are persistent, not episodic, and present when youth are euthymic, whereas bipolar symptoms are intermittent and an alteration from baseline. Elevated mood, euphoria, decreased need for sleep, and inappropriate sexual behaviors are more prevalent in BD than ADHD,26 and in BD should resolve after the mood episode. ADHD typically presents in early elementary school, whereas BD usually presents from mid-adolescence to young adulthood
||ODD is characterized by angry/irritable mood, argumentative/defiant behavior, and/or vindictiveness in a frequent and persistent pattern. This is in contrast to the episodic and sporadic nature of BD. Comorbid ODD is common in ADHD
||Temper outbursts and irritable/angry mood between outbursts are frequent and persistent in DMDD, whereas BD mood symptoms and behavior changes are episodic and a change from baseline. Elevated mood and grandiosity are common in BD but not characteristic of DMDD. According to DSM-5, youth meeting criteria for DMDD and ODD or intermittent explosive disorder should be diagnosed with DMDD only, whereas youth meeting criteria for DMDD and BD should be diagnosed with BD only