Update on Pediatric Bipolar Disorder

Transcription

1 Update on Pediatric Bipolar Disorder Lisa D. Townsend, MSSA, LSW, Christine A. Demeter, MA, Michael Wilson, MD, and Robert L. Findling, MD Corresponding author Robert L. Findling, MD Child and Adolescent Psychiatry, University Hospitals Case Medical Center, Euclid Avenue, Cleveland, OH , USA. Current Psychiatry Reports 2007, 9: Current Medicine Group LLC ISSN Copyright 2007 by Current Medicine Group LLC Children and adolescents with a bipolar disorder experience mood dysregulation that is often chronic with little interepisodic recovery. Although bipolar disorder in youth is recognized by more and more clinicians, much is still not known regarding how best to accurately diagnose and effectively treat it. As a result, children and adolescents with bipolar disorder are often symptomatic for long periods of time before receiving appropriate treatment. In this review of the pediatric bipolar disorder literature, the phenomenology, longitudinal course, and risk factors associated with the illness development are discussed. Also, recent research pertaining to neuroimaging and pharmacologic and psychological treatments are considered. Because pediatric bipolar disorder is such a pernicious condition, it is recommended that clinicians complete a careful assessment of mood symptoms and comorbid conditions when this illness is suspected so that they can provide treatments with the best chance of benefit in a timely manner. Introduction Significant controversy exists in child and adolescent psychiatry regarding the prevalence, clinical presentation, and treatment of pediatric bipolar disorder (PBD). Although consensus has emerged that the condition exists and is impairing to youth, considerably less agreement exists about how to best diagnose and treat this pernicious disorder. This review summarizes the extant knowledge about PBD, including clinical presentation, longitudinal course, comorbidity and differential diagnosis, treatment, and emerging neuroimaging data. Epidemiology Lifetime prevalence rates of bipolar illness in adults range from 0.4% (bipolar I only) to 6.0% (broad spectrum of disorders) of the population [1]. Prevalence rates in youth have been more difficult to determine given that the illness clinical presentation rarely resembles the classical clinical presentations exhibited by adults [2]. Most pediatric cases that come to clinical attention appear to meet diagnostic symptom criteria for bipolar disorder-not otherwise specified (BP-NOS) or cyclothymia [3 ], reflecting a lack of clearly demarcated mood episodes meeting the duration criteria required for bipolar I or II disorders. Up to one third of adults with a bipolar disorder identify their first onset of symptoms in childhood or adolescence in studies using retrospective recall methods [4]. Therefore, it appears that a substantial number of adults do have illness onset during childhood or adolescence. However, another possible explanation for this high rate, based on adult retrospective recall, may be the fact that symptom overlap exists between bipolar illness and other, more common childhood/adolescent psychiatric disorders, such as attention-deficit/hyperactivity disorder (ADHD) or disruptive behavior disorders. These disorders in turn increase the risk of bipolar disorder in young adult life. As a result of this symptom overlap, these adult patients ability to accurately identify the onset of bipolar disorders may be impaired. Clinical Presentation One of the most significant challenges for practitioners is diagnosing PBD accurately, given that the typical presentation of bipolar illness in youth may differ dramatically from that of adults. Also, the symptoms of pediatric bipolar illness need to be differentiated from normal childhood development (eg, a child aged 5 years pretending to have superpowers) and from other disorders that have overlapping symptoms (eg, the hyperactivity that is characteristic of ADHD) [3 ]. Furthermore, assessment must account for the possible existence of a bipolar spectrum illness that is presenting with one or more comorbid psychiatric disorders. One of the areas of greatest distinction between youth and adult bipolar disorders is mood episode duration. Whereas adults prototypically present with distinct, demarcated episodes of mania and depression, youth tend to exhibit chronic mood dysregulation with little interepisode remission. A substantial proportion of youth present with histories and symptoms that meet criteria for BP-NOS rather than bipolar I or II disorders [5]. Nevertheless, it

2 530 Bipolar Disorders appears that the majority of youth with bipolar spectrum illness remain symptomatic over time [6 ]. The presence of other psychiatric illnesses may precede the syndromal expression of bipolar disorder. Reported predictors of mania include a depressive episode with rapid onset, presence of psychomotor retardation or psychosis, a family history of affective disorders, and a history of mania after treatment with antidepressants [7]. Additionally, adult and pediatric bipolar disorders have qualitatively different symptom presentations. The role of irritability versus euphoria has been debated in the literature. Whereas adults often present with euphoria or grandiosity, extreme irritability and explosive anger have been commonly described in PBD [8 ]. Some researchers still include grandiosity as a requisite indicator of mania in youth, along with other characteristic symptoms such as elevated mood, racing thoughts, decreased need for sleep, and hypersexuality [9]. Across multiple phenomenological studies, it seems that no single symptom is considered specifically indicative of mania; rather, a constellation of symptoms is needed to make an accurate diagnosis [10 ]. Evaluating differential diagnoses and comorbidities also is critical in recognizing pediatric presentations of bipolar illness. This is because psychiatric comorbidities seem to be the rule and not the exception in pediatric bipolarity. The most common comorbid diagnosis appears to be ADHD [10 ], which shares several overlapping symptoms with mania (distractibility, hyperactivity, and increased speech). Bipolar illness and conduct disorder also share substantial symptom overlap, including aggressive and destructive behaviors. Further complicating the diagnostic picture, substance abuse or anxiety disorders may generate the appearance of mania. Delusions and thought disorder may be misinterpreted as signs of schizophrenia. To address these complicated diagnostic issues, it has been recommended that a thorough assessment be conducted adhering to DSM-IV criteria. The American Academy of Child and Adolescent Psychiatry s practice parameter for bipolar disorder notes that clinicians also should incorporate a thorough developmental and symptom history, assessing behavior patterns across multiple settings and ascertaining how symptoms developed [3 ]. Interviews with youth and parents are considered vital given the low concordance that may exist between parents and youth regarding internalizing symptoms such as depressive cognitions, racing thoughts, and behaviors not always readily observed (eg, reduced need for sleep). It also is important that youth suspected of having bipolar illness be monitored for emergence of suicidality, substance abuse, comorbid diagnoses that further impair functioning, and intercurrent psychosocial stressors [3 ]. Longitudinal Course The literature to date indicates that the long-term outcome for youth with PBD is similar to and often worse than that of patients with an adult onset of bipolar disorder [11]. It has yet to be confirmed by careful longitudinal studies that youth with PBD eventually will develop more classic or adult-like presentations of bipolar illness as they mature. However, what is known is that pediatric BPD is characterized by a chronic illness course punctuated by frequent relapses [6,12,13]. Youth with PBD frequently remain symptomatic, spending substantial portions of their lives experiencing subsyndromal or fully syndromal mood symptoms [6 ]. Risk factors for poor outcomes once PBD has been diagnosed are low socioeconomic status, presence of rapid cycling, presence of mixed episodes, comorbid psychiatric illnesses, family psychopathology, and family conflict [14]. Early age of onset and psychosis also are associated with poor outcomes [6 ]. Furthermore, bipolar disorders in youth may place these patients at risk for physical or psychosocial trauma given these individuals symptoms of distractibility, risk taking, impulsivity, and aggressive behavior. Risk Factors for Developing PBD Family studies demonstrate that bipolar illness occurs more frequently among biological relatives than in the general population [2]. High incidence of psychiatric illness has been reported in youth whose parents have bipolar disorder [15]. Children of parents with bipolar illness exhibit greater incidence of disruptive behavior disorders and depression than normal controls [16]. Youth with parents suffering from bipolar illness display more symptoms suggestive of early-onset bipolar illness, including anxiety, depression, irritability, school problems, and mood reactivity [15,16]. Genetic studies provide strong evidence that bipolar illness is a heritable disorder [17]. Generational studies show that bipolar disorder symptoms occur at earlier ages and with increasing severity in successive generations of families with the diagnosis, a finding suggestive of the phenomenon of genetic anticipation [18]. However, to date, no specific genes or genetic mechanisms have been associated definitively with development of pediatric bipolar spectrum illness. Neuroimaging and Neurocognitive Studies Functional and structural neuroimaging studies provide compelling evidence that biological underpinnings to PBD exist. Some areas of structural differences that have been reported between youths with PBD and healthy controls include the thalamus, amygdala, hippocampus, superior temporal gyrus, and cerebral cortex [19]. Also, structural neuroimaging studies have provided data suggesting that pharmacotherapy may have protective effects in patients suffering from bipolar illness [20]. Magnetic resonance spectroscopy has provided additional evidence of neurobiological differences between youth

3 Update on Pediatric Bipolar Disorder Townsend et al. 531 with PBD and healthy controls [19]. For example, youth diagnosed with bipolar disorder showed significantly higher myoinositol/creatine-phosphocreatine ratios and myoinositol in the anterior cingulated cortex when compared with youth with intermittent explosive disorder and healthy controls [21]. Also, youth with PBD who were clinically stable on medication demonstrated lower right dorsolateral prefrontal cortex N-acetylasparate/creatine ratios in comparison with youth who had no psychiatric diagnoses [22]. Furthermore, Moore et al. [23] found that unmedicated youth with bipolar disorder had significantly lower glutamine levels in the anterior cingulate cortex compared with patients with a bipolar disorder who were receiving medications and those without a psychiatric diagnosis. Neurocognitive studies provide additional evidence that differences exist between youths with PBD and controls. Children and adolescents with bipolar disorder, regardless of medication status, have shown impairment in attention, executive function, working memory, and verbal memory compared with healthy controls [24]. However, others have questioned whether the neurocognitive difficulties experienced by young patients with bipolar disorder are predominantly due to the ADHD comorbidity that is commonly seen [25]. Relatively few functional neuroimaging studies have been performed in youths with bipolar disorder. Some of these functional MRI studies have focused on neurocognition. Blumberg et al. [26] noted increased activation of the left putamen and thalamus in youth with bipolar disorder compared with children and adolescents without a psychiatric disorder during the performance of the Stroop task. In addition, during the completion of a working memory task, youths with bipolar disorder, when compared with controls, have had differences in activation that were evident in several brain regions [27]. Also, it has been reported that children with PBD may misinterpret sad, happy, and fearful facial expressions more often when compared with youth with anxiety disorders and those with no psychiatric diagnosis, suggesting that youth with PBD may overperceive anger in social interactions with peers [28]. A possible biological underpinning for the misinterpretation of facial expression also has been examined using functional MRI. For example, Rich et al. [29] found that youth with bipolar disorder perceived more hostility and experienced more anxiety than controls when viewing neutral faces. Pharmacologic Treatment and Electroconvulsive Therapy No medication currently carries US Food and Drug Administration approval for treating all phases of PBD [3 ]. The general consensus from clinical trials to date emphasizes use of mood stabilizers (lithium or anticonvulsants) and atypical antipsychotics for acute stabilization of manic symptoms and maintenance of symptom remission [3 ]. The majority of studies conducted have been open-label trials, although a few have been double-blind, placebo-controlled investigations. Geller et al. [30] found significantly greater benefit for lithium than placebo in reducing substance abuse rates in youth suffering from comorbid bipolar and substance abuse disorders. There are placebo-controlled data to suggest that olanzapine is superior to placebo in the acute treatment of adolescents with mania [31]. An underpowered, placebocontrolled study suggests that topiramate may be effective in the acute treatment of pediatric mania [32]. Also, there is another unpublished, acute, randomized controlled study that showed that divalproex sodium therapy was not superior to placebo treatment in this patient population [33]. Kafantaris et al. [34] examined lithium versus placebo in a discontinuation trial, finding no difference in relapse into mania 2 weeks after lithium therapy cessation. Findling et al. [35] found no difference between lithium and divalproex sodium for maintenance therapy in youths who had responded initially to combination pharmacotherapy. Combination therapy has been studied even less extensively. Findling et al. [36,37] demonstrated that combination treatment with lithium and valproate was effective for acute stabilization of manic symptoms. Quetiapine combined with valproate demonstrated greater efficacy in treating manic symptoms than quetiapine combined with placebo [38]. In another study, combination therapy with mood stabilizers plus antidepressants, antipsychotics, or stimulants was associated with improvements in affective symptoms for patients who remained symptomatic while being prescribed drug monotherapy [39]. Particular consideration must be given to pharmacologic treatment of depression in youth with bipolar illness given the propensity of these youth to switch into mania during antidepressant monotherapy. Baumer et al. [40] found that 64% of bipolar youth had an adverse psychiatric reaction (elevated mood, expansiveness, irritability) to antidepressants within 3 months of initiating treatment. Current consensus indicates that antidepressants, if they are prescribed, should be used as an adjunct to mood stabilizers to treat depressive symptoms in youth with PBD [41]. Similarly, it appears that treating comorbid ADHD symptoms also should be approached with some caution. It generally is recommended that ADHD, one of the most common comorbid diagnoses, is best treated by combining psychostimulant therapy with concomitant mood stabilizers [41]. Two double-blind, placebo-controlled studies have demonstrated successful ADHD symptom treatment while maintaining mood stability. Findling et al. [42] found that methylphenidate in conjunction with mood stabilizers significantly improved ADHD symptoms while maintaining remission of affective symptoms. Similarly, Scheffer et al. [43] showed that valproate combined with mixed amphetamine

4 532 Bipolar Disorders salts was superior to valproate plus placebo in treating ADHD symptoms. As for pharmacotherapy duration, it currently is recommended that treatment with mood stabilizers be maintained for 12 to 24 months after acute manic symptom stabilization [41]. However, it remains unclear whether pharmacotherapy in youth alters the disorder s longitudinal course with age. Electroconvulsive therapy has been used to treat bipolar disorder in adults, but it has not been extensively studied in youth. No methodologically stringent investigations of this treatment modality exist in youth. Although case reports suggest benefit for treatment-resistant patients, this modality is only recommended for youth who have severe symptomatology, have exhausted other treatment options with no response, or for whom pharmacotherapy is contraindicated [41]. Psychosocial Treatment Psychosocial treatments are recommended to help ameliorate bipolar illness negative impact on family and peer relationships and to augment symptom remission for youth with comorbid oppositional defiant or conduct disorders [3 ]. Youth with bipolar illness often exhibit poor social skills, have fewer friends, and experience higher degrees of conflict with family members and peers. They also exhibit greater degrees of anger, hopelessness, and difficulties in coping with life stressors. Four types of psychotherapeutic intervention have been examined in youth with bipolar illness: psychoeducation, family-focused therapy, cognitive-behavioral therapy, and interpersonal social rhythm therapy (IPSRT). Family psychoeducation focuses on educating parents and youth about bipolar illness; ameliorating caregiver and parent-child discord about how to manage symptoms and treatment; teaching youth to improve their social skills; and implementing family stress-reduction techniques, with significant improvement in symptom severity and family discord [44]. Fristad et al. [45] evaluated this paradigm s impact in a six-session, multifamily psychoeducation group for children diagnosed with unipolar depression or bipolar disorder. Parents reported significant decreases in negative attitudes toward their children and fewer dysfunctional parenting behaviors. Similarly, parents who participated in a brief psychoeducation workshop reported decreased levels of emotional intensity [46]. Family-focused interventions emphasize psychoeducation, communication skills, and family problem solving [47]. A group of 20 bipolar youth participating in a family-focused intervention demonstrated a 38% improvement on a depression rating scale and a 46% improvement on a mania rating scale after 9 months of intervention with their families [48,49]. Cognitive-behavioral interventions for parents and youth with PBD focus on challenging negative thoughts, establishing daily routines, using social supports, and regulating affect [50]. Each therapy component is applied to youth and parents, with some work completed individually and some work completed in family sessions. An initial pilot study with 34 youth demonstrated significant improvement in symptoms and overall functioning [51]. IPSRT teaches individuals with bipolar illness to understand areas of interpersonal conflict with others, cope with grief regarding their psychiatric diagnosis, negotiate social roles effectively, and regulate their sleep and social routines [52]. A randomized trial comparing IPSRT with other psychosocial treatments in adults demonstrated a significant impact on patients ability to implement regular sleep and social schedules and showed longer maintenance of stable mood [53]. IPSRT is being adapted for use with adolescents, but pilot studies are not yet completed. Conclusions As can be seen by this overview, although what is known about PBD is increasing, much still needs to be learned about this condition. This review also highlights areas of need for further research: improving diagnostic accuracy, documenting long-term outcomes for youth with PBD, improving pharmacologic management, and establishing psychosocial interventions as routine adjuncts to pharmacotherapy in hopes of improving youths social functioning while decreasing symptom severity and reducing the human suffering associated with this serious and chronic condition. Acknowledgments Dr. Findling has received research support, served as a consultant, and/or served on the speakers bureau for Abbott Laboratories, AstraZeneca Pharmaceuticals, LP, Bristol-Myers Squibb, Cypress Bioscience, Inc., Forest Laboratories, Inc., GlaxoSmithKline, Inc., Johnson & Johnson, Eli Lilly and Co., Neuropharm Group, PLC, New River Pharmaceuticals, Inc., Novartis Pharmaceuticals, Organon, Inc., Otsuka America Pharmaceutical, Inc., Pfizer, Inc., Sanofi-Aventis, Sepracor, Inc., Shire, Solvay Pharmaceuticals, Supernus Pharmaceuticals, Inc., and Wyeth. References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, edn 4, text revision (DSM-IV-TR). Washington, DC: American Psychiatric Association; Pavuluri MN, Birmaher B, Naylor MW: Pediatric bipolar disorder: a review of the past 10 years. 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5 Update on Pediatric Bipolar Disorder Townsend et al McClellan J, Kowatch R, Findling RL, et al.: Practice parameter for the assessment and treatment of children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2007, 46: This practice parameter provides suggestions by which recent research findings may be successfully incorporated into clinical practice. 4. Goldstein BI, Levitt AJ: Further evidence for a developmental subtype of bipolar disorder defined by age at onset: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Am J Psychiatry 2006, 163: Axelson D, Birmaher B, Strober M, et al.: Phenomenology of children and adolescents with bipolar spectrum disorders. Arch Gen Psychiatry 2006, 63: Birmaher B, Axelson D, Strober M, et al.: Clinical course of children and adolescents with bipolar spectrum disorders. Arch Gen Psychiatry 2006, 63: A large-scale study examining the longitudinal course of pediatric bipolar illness. 7. 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