Mani N. Pavuluri, MD, PhD

Note: This article was originally presented as an independent educational activity under the direction of CME LLC. The ability to receive CME credits has expired. The article is now presented here for your reference. 

After reading this article, you will be familiar with:

• The pathophysiology of pediatric bipolar disorder (PBD)
 • Assessment tools and measures
 • Treatment options
 • Comorbidities
 
 

Who will benefit from reading this article?


 Psychiatrists, child and adolescent psychiatrists, psychologists, primary care physicians, nurse practitioners, and other health care professionals. To determine whether this article meets the continuing education requirements of your specialty, please contact your state licensing and certification boards.

Pediatric bipolar disorder (PBD) is a serious psychiatric illness that impairs children’s emotional, cognitive, and social development. PBD causes severe mood instability that manifests in chronic irritability, episodes of rage, tearfulness, distractibility, grandiosity or inflated self-esteem, hypersexual behavior, a decreased need for sleep, and behavioral activation coupled with poor judgment. While research in this area has accelerated during the past 15 years, there are still significant gaps in knowledge concerning the prevalence, etiology, phenomenology, assessment, and treatment for PBD.

This article briefly summarizes the scientific evidence that has contributed to our understanding of this disorder. The research literature in the areas of prevalence, etiology, pathophysiology, assessment, diagnosis, and treatment is reviewed.

Unfortunately, there are still no authoritative data on the prevalence of PBD: estimates depend on whether the disorder is defined as a narrow or broad phenotype.

 Children with the narrow phenotype fit symptom criteria for a bipolar disorder diagnosis as defined by 

, whereas children with the broad phenotype experience serious mood dysregulation and associated symptoms but may not meet symptom number or duration criteria defined by the narrow phenotype.

One community study showed a lifetime prevalence of bipolar disorder of 1% in youths aged 14 to 18 years, using the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS).

 found the lifetime prevalence of severe mood dysregulation to be 3.3% in children aged 9 to 19 years from an epidemiological study sample. These findings indicate that a high percentage of the population may experience symptoms consistent with the broad phenotype of PBD.

Retrospective studies of adults with bipolar disorder have reported that as many as 60% experienced symptoms before age 20 years and 10% to 20% reported symptoms before age 10 years.

It remains unclear, however, how subthreshold symptoms in childhood relate to adult-onset bipolar disorder, as well as whether there is continuity between the childhood-onset presentation and the more classic presentation of adult bipolar disorder.

 showed continuity in both disorder presence and nature of symptoms in children with bipolar I disorder who were observed for 8 years into adulthood. The findings from their study indicate that the unique symptom presentation of early-onset bipolar disorder continues into adulthood for these children.

Despite a lack of knowledge on exact prevalence and the continuity or overlap between childhood-onset and adult-onset presentations, the psychosocial and interpersonal effects of PBD (whether broad or narrow phenotype) on patients and their families is devastating. A community study showed that PBD is associated with substantial impairment in social (66%), family (56%), and school (83%) functioning.

 PBD has been associated with behavioral problems in school, low grades, having few or no friends, frequent teasing, poor social skills, poor sibling relationships, and parent-child relationships characterized by frequent hostility and conflict.

Heritability for PBD is substantially high with a rate of 15% to 42% risk in first-degree relatives of children with PBD.

There is some evidence to indicate gene linkages with the brain-derived neurotrophic factor (BDNF) gene (

), the glutamate decarboxylase 1 (GAD1) gene (

). However, none of these associations has been replicated and the sample sizes in these studies significantly limit the detection of small effects.

 Furthermore BDNF in platelets has been shown to be decreased in PBD and increased with treatment.

Although the pathophysiology of PBD remains unknown, MRI studies during the past 5 to 10 years have significantly advanced scientists’ understanding of the brain mechanisms related to PBD symptoms and associated impairments. Structural and functional studies have all shown frontostriatal and frontolimbic abnormalities relative to healthy controls. A consistent structural finding is a small amygdala.

There are extensive abnormalities in other related brain regions; overall findings implicate abnormalities in regions of the cognitive, emotional, and reward systems.

 White matter tract integrity is affected in the prefrontal regions of the corticobulbar tracts in patients with PBD relative to healthy peers.

A 3-year longitudinal study demonstrates that neurocognitive deficits persist in PBD and show no change during the 3 years in the areas of executive function and verbal memory. While there is improvement in working memory and attention, children with PBD do not catch up with their healthy peers.

 It is important to evaluate whether there are academic difficulties related to poor neurocognitive abilities.

Assessment and diagnosis of PBD have also advanced rapidly during the past 15 years. Whereas the notion of diagnosing bipolar disorder in childhood has been plagued by controversy in the past, the literature base to date has led to a consensus that PBD represents a discrete cluster of symptoms that can be validated by reliable assessment.

 The question remains as to how to best classify and describe the heterogeneity in clinical presentation seen in children with early-onset bipolar disorder.

The diagnosis of PBD is complex and requires an in-depth evaluation of the current presenting problem, as well as a history of mood episodes during the child’s lifetime to assess chronicity and episodicity. A clinical interview for making a diagnosis is still the gold standard. In research, however, a diagnostic clinical interview (eg, Washington University in St Louis Kiddie Schedule for Affective Disorders and Schizophrenia [WASH-U-KSADS] or Kiddie-SADS–Present and Lifetime Version [K-SADS-PL]) is often supplemented by an in-depth developmental history and multi-informant clinical rating scales to determine global functioning, social and academic impairment, and quality-of-life issues.

Screening measures can be used preliminarily to assess the presence of different types of manic symptoms. The Child Mania Rating Scale–Parent version (CMRS-P) is the first rating scale that was designed and tested specifically to screen for PBD.18 This measure has 21 developmentally specific items corresponding to 

–based symptoms. A score of 15 or more (of a potential total score of 63) indicates a 92% chance of having PBD. The CMRS-P is a screening instrument with excellent psychometric properties and is available in 12 languages. It is intended to facilitate early identification of PBD with the hope of aiding parents who seek help for their child, but it is not a diagnostic tool.

Once a formal diagnosis of PBD is made, additional evaluation is needed to address systemic problems through psychosocial treatment that complements pharmacotherapy. Issues include:

• The level of distress of the patient and the family

• Knowledge, skills, and attitude of parents

• The child’s school functioning and neurocognitive problems

Bipolar I disorder is diagnosed if a child manifests abnormally elevated mood, grandiosity or inflated self-esteem, extreme irritability, hypersexuality (not explained by a history of sexual abuse), decreased need for sleep, and behavioral activation (characterized by agitation and pressured speech) coupled with poor judgment. Elevated mood, grandiosity, and irritability are the core symptoms of mania. While there is some debate about which of these is most central to a bipolar I disorder diagnosis, irritability interspersed with rage episodes tends to be the most readily identified and problematic for parents.

The 2009 Roundtable on Bipolar Disorder in Children and Adolescents recommends that a diagnosis be based on DSM-IV criteria, which require that children demonstrate 1 core symptom and 3 additional symptoms (4 if core symptom is irritability).

The symptoms must represent a deviation from the child’s baseline and from age-appropriate behavior. The episode must meet the duration criteria of 7 days for mania and 4 days for hypomania, and symptoms must persist for at least 4 hours each day.

The differentiation of elation and grandiosity from developmentally normative silliness and self-aggrandizement can be challenging. Other mania symptoms, such as hypersexuality and impulsivity, may also present in unique ways, depending on the child’s developmental stage. Symptom expressions such as inflated self-esteem and increased goal-directed activity are best judged in the context of the child’s history because behaviors may be misleading in isolation and must be considered in the context of the child’s cognitive, biological, and social development. If several of the symptoms exist together, however, and are episodic with impairment in functioning, then PBD should be considered.

Bipolar II disorder presents with major depressive episodes that alternate with hypomanic episodes; however, the depressive episodes are central to the clinical picture and cause significant dysfunction. It is often hard to characterize hypomania in youth, given developmentally appropriate excitability.

Youths with bipolar disorder not otherwise specified (NOS) either have fewer symptoms or have symptoms of shorter duration or less intensity than those required to meet full 

 diagnostic criteria. As many as 35% of children with onset at a younger age meet criteria for bipolar disorder NOS.

 To distinguish between bipolar I disorder and bipolar disorder NOS, it is important to clearly establish cycling or episodicity or both and not to confuse episodes with cycles.

The discovery of the unique phenomenology of PBD led to the description of ultradian cycling in children, defined as cycling at least once within a day (or more than 365 cycles a year).

 should be differentiated from the rapid cycling variants of bipolar disorder as characterized by Geller and colleagues.

, rapid cycling is defined as having more than 4 episodes of depression or mania or mixed state during a 1-year period. In phenomenological studies conducted by Geller and colleagues,

 parents often described mood dysregulation in their young children as rapid mood swings, sometimes multiple times a day. This discovery of the unique phenomenology of PBD led to the description of ultradian cycling in children, defined as cycling at least once within a day (or more than 365 cycles a year).

The discrete episodes (of mania, mixed symptoms, hypomania, and depression) with respite in between that are seen more often in the adolescent and adult-onset presentation clearly exist in some children, but they are are less common. In children, respite between episodes is less common, and often children experience subsyndromal symptoms or chronic impairment. Symptom respite in between recurrent episodes depends on severity of illness, availability of proper treatment, and the ability of the family to successfully manage the illness.

Mixed episodes and comorbid attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder, and anxiety are common in PBD. A good rule of thumb for determining whether a symptom represents true comorbidity or is part of bipolar disorder is to evaluate whether it appears to be rooted in mood disturbance (ie, whether it intensifies with mood fluctuation). Also, bipolar disorder NOS evolves into bipolar I or II disorder in some children as they mature. One study found that bipolar disorder NOS evolved into bipolar I or II disorder in 38% of youths during a 4-year period.

It is critical to define the “signature of the illness” for each child. In addition, the pattern of symptom experience, onset and offset, and timeline of episodes help establish the diagnosis. A comprehensive developmental history is essential to understand the emergence of symptoms in a developmental context. For example, there is some evidence that PBD diagnosis may be preceded by a difficult temperament style in infancy and toddlerhood compared with children without PBD.

Comorbid ADHD is diagnosed if symptoms precede the onset of PBD symptoms or if the child has very early-onset PBD with symptoms of ADHD that do not resolve after successful treatment of the PBD; however, it is possible that these symptoms represent residual symptoms of intrinsic overactivity and inattention observed in PBD. A family history of bipolar disorder, given the familial risk, adds value in considering the diagnosis.

 However, that family history should not be considered as a diagnostic feature. Conversely, the absence of a family history does not rule out the diagnosis of PBD.

Evidence suggests that a combination of atypical antipsychotics or mood stabilizers or both is effective in the treatment of mania in PBD.

 Some children may need to have medications added to the primary mood stabilizer to treat comorbid symptoms of attention deficit, aggression, anxiety, psychosis, and sleep disturbance; however, efficacy results remain mixed.

 integrated the current evidence updated from the previously published evidence-based pharmacotherapy algorithm. The basic tenets of this approach are:

• Prescription hygiene (ie, discontinuation of medications that are worsening the clinical state)

• Overcoming obstacles to mood stabilization by addressing breakthrough symptoms

• Problem solving for comorbid conditions or adverse medication effects or both

A pharmacotherapeutic plan for mood stabilization consists of 2 parts. The first is a history of medications that worsened the patient’s clinical status, those that were ineffective, and those that were transiently useful or helpful; the second is the discontinuation of all ineffective medications.

There is no evidence to show which patients worsen with stimulants and which do not. Mood stabilization is the primary treatment objective in PBD; controlling symptoms of ADHD is secondary. However, if the patient’s parents report that stimulants have been helpful and there is a clear pattern of response independent of affect dysregulation, a long-acting stimulant at the lowest dose may be prescribed.

The treatment of choice for mood stabilization is either an atypical antipsychotic, such as risperidone or aripiprazole-which has been FDA-approved for children as young as 10 years-or mood stabilizers, such as lithium (FDA-approved for youths older than 12). Data on quetiapine, olanzapine, and ziprasidone have been presented to the FDA; these agents may be used off label for children and adolescents aged 10 through 17 years.

Articles

The State of the Evidence on Pediatric Bipolar Disorder

Psychiatric Times May 2005 Vol. XXII Issue 6

Given the hectic pace of clinical practice, it is difficult to keep up with the research on pediatric bipolar disorder (PBD). This is particularly true in the area of pharmacological management. An effective, evidence-based algorithm for the pharmacological treatment of PBD will offer support for clinical decision making. For example, a single mood stabilizer has been shown to be ineffective in more than 50% of cases (DelBello et al., 2002; Kafantaris et al., 2001a, 2001b). Furthermore, a systematic approach to medication management will prove useful in updating a patient's treatment when faced with the development of medication tolerance. Finally, this framework will provide doctors with powerful means of collaborating with families. Our preliminary studies have also demonstrated effectiveness of integrating psychotherapy that is based on validating parents and children, while effectively solving problems related to affect dysregulation (Pavuluri et al., 2004a).

Pediatric bipolar disorder manifests differently from adult BD. It can be quite difficult to differentiate between actual grandiosity and the fatuous self-aggrandizement that can arise out of insecurity. It is critical to ask specifically about symptoms of psychosis and hypersexuality. Parents and children rarely report these symptoms spontaneously. However, if several of these symptoms appear together, causing dysfunction with substantial mood dysregulation, PBD must be considered.

Bipolar II disorder (BD-II) tends to present with major depressive episodes alternating with hypomanic episodes. Parents often described mood dysregulation as rapid mood swings (Geller et al., 1995). Given the consistency of these reports, the researchers attempted to integrate this description into the phenomenology of PBD. However, PBD can often be non-episodic and chronic (Geller et al., 2004), especially if left untreated. Mixed episodes and comorbid attention-deficit/hyperactivity disorder and anxiety are very common in PBD. Oppositional defiant disorder is reported to be present in many youth with PBD, but cannot be diagnosed according to strict criteria in the face of PBD. Such symptoms may represent a reactive phenomena originating from PBD.

Symptoms, pattern of onset and offset, and timeline will help the clinician establish the diagnosis. Comorbid ADHD is diagnosed if it precedes the onset of PBD symptoms or if the child has very early onset PBD with unresolved ADHD after successful PBD treatment. However, it is possible that these symptoms represent residual intrinsic over-activity and inattention observed in PBD. Family history of BD adds value in considering the diagnosis (Faraone et al., 2003). However, family history should not be considered a diagnostic feature. Conversely, the absence of a family history does not rule out the diagnosis of PBD.

The Child Mania Rating Scale-Parent version (CMRS-P) is the first rating scale designed and tested specifically to screen for PBD (Pavuluri et al., 2004b). It has 21 developmentally specific items corresponding to 

 symptoms. A score of >15 (out of 63) indicates a 92% chance of having the diagnosis. However, it is not a diagnostic tool.

Basic principles of this algorithm model consist of prescription hygiene, mood stabilization, addressing breakthrough symptoms and problem solving.

. In establishing a pharmacotherapeutic plan for mood stabilization, four things are important to consider. First, a history should be obtained. Second, rapidly wean off all ineffective medications. Third, discontinue selective serotonin reuptake inhibitors. Despite compelling data in pediatric populations of SSRIs worsening symptoms by either switching to or worsening mania (Biederman et al., 2000), several families bring in children on substantial doses of SSRIs. Fourth, stimulants should be discontinued. However, given the equivocal data (Carlson and Kelly, 1998; Carlson et al., 2000; Scheffer et al., 2005) and the negative influence of stimulants (DelBello et al., 2001; Mota-Castillo et al., 2001; Soutullo et al., 2002), if parents report that stimulants have shown a pattern of response, independent of affect dysregulation, it is advised to continue them but at lowest possible doses and in long-acting form.

. The first treatment of choice continues to be a mood stabilizer such as lithium (Eskalith, Lithobid) or divalproex (Depakote), due to an established track record mainly based on studies of adult BD. Lithium or divalproex may not always be effective in PBD and/or may slow onset of action. Consequently, second-generation antipsychotics (SGAs) are rapidly finding their place either as monotherapy (in emergencies where stabilizing mania is a priority) (DelBello et al., 2004; Frazier et al., 2001) or in combination with a mood stabilizer (Kowatch et al., 2003; Pavuluri et al., 2004c, 2004d). The SGAs alone may be effective when irritability is prominent and demands a faster response not possible with first-line mood stabilizers (Pavuluri et al., 2004d). Combination therapy of SGAs plus lithium or divalproex is an effective first-line strategy for severe cases, especially those with psychotic features (Kafantaris et al., 2001a, 2001b). This strategy has the advantage of needing lower doses of SGAs compared to doses potentially required for monotherapy, resulting in far less severe adverse events.

, we propose a sequence of medication choices in each group and their rationales. While these tables provide a basic guideline, the clinician needs to use their discretion in individual cases. (Prescribing information is summarized in Pavuluri and Janicak [2004]).

. Pediatric bipolar disorder presents a multitude of clinical challenges beyond acute mood stabilization that must be factored into both the acute and maintenance phases of treatment.

. If there are prominent symptoms of depression, lithium or lamotrigine (Lamictal) are chosen as primary mood stabilizers either alone or as adjuvant to other partially effective agent (Bowden, 2002; Calabrese et al., 2000). The second choice would be a combination of lithium plus lamotrigine. The third choice is a small dose of SSRI (in severe depression). A long-acting medication and psychoeducation are often effective (Wilens et al., 2003). It is important to balance the risks versus benefits, given the "black-box" warning associated with SSRI use in children.

. The SGAs must be added to the regimen, working down the list as indicated in 

. Switch to SGA monotherapy if mild aggression is present. In moderate to severe presentations, a combination of mood stabilizer and SGA is used (

). Clonidine (Catapres) can be used to subdue rage attacks (Prince et al., 1996). However, children can become disinhibited or become more aroused after persistent use, although this particular observation needs to be further examined.

. Chronic unremitting symptoms must be treated by: 1) alternative monotherapy; 2) at least two trials of combination regimes of mood stabilizers plus SGA; and 3) triple therapy addressing comorbid conditions.

. It is customary for the clinician to take advantage of increasing the p.m. dose of a sedating mood stabilizer. Beyond that, melatonin 1 mg to 3 mg (Smits et al., 2003), tiagabine (Gabatril) 5 mg (Gustavson et al., 1997; Mathias et al., 2001) or trazodone (Desyrel) 150 mg (Balon, 1994; Saletu-Zyhlarz et al., 2003, 2001) can be administered to establish a proper sleep routine that is critical in PBD. While these compounds are not empirically supported by research specifically on sleep disorders in PBD, they are known to be sedative, safe in pediatric populations, and to interfere minimally with rapid eye movement sleep. In subjects with abuse potential, benzodiazepines may be misused and medications such as trazodone may be effective alternatives (Rush et al., 1999).

. While ADHD is a distinct disorder from PBD, it is not understood if the ADHD-like symptoms in PBD warrant additional treatment beyond mood stabilization. In our study, several subjects continued to show symptoms of inattention post-mood-stabilization that warranted stimulant medication (Pavuluri et al., 2004d). Stimulants are almost always given in long-acting form unless an additional after-school dose is required to sustain the benefits. Methylphenidate (Ritalin long-acting, Concerta) or mixed amphetamine salts (Adderall) are equally effective. Atomoxetine (Strattera) is an alternative treatment if stimulants have been ineffective (Pavuluri et al., 2004d). There are no data establishing safety or efficacy of atomoxetine in treating comorbid ADHD and PBD. Atomoxetine is a selective norepinephrine reuptake inhibitor with potential antidepressant effects and could theoretically trigger or exacerbate symptoms of mania.

. Anxiety disorders, including generalized anxiety disorder and separation anxiety disorder, are relatively common, especially in bipolar I disorder. Psychotherapeutic interventions, such as cognitive-behavioral therapy (CBT), remain the first choice of treatment for comorbid PBD and anxiety disorder. The SSRIs are the only medications consistently shown to be effective in controlled trials for childhood anxiety disorders (Birmaher et al., 2003; Black and Uhde, 1994; Research Unit on Pediatric Psychopharmacology Anxiety Study Group, 2001). This treatment requires educating the family about the risk of a manic switch, and close monitoring of treatment response is necessary. Benzodiazepines (Bernstein et al., 1990; Graae et al., 1994; Simeon et al., 1992) and buspirone (BuSpar) follow as alternative choices. Risk for developing dependence needs to be considered with long-term use of benzodiazepines in adolescents. Buspirone may not be effective in all cases. Propranolol (Inderal) may be considered in cases of performance anxiety.

. Low doses and slow titration are two fundamental principles that keep adverse events to a minimum. If problems continue, switching to an alternative medication may be necessary. Despite several antidotes for weight loss, the single most important intervention is diet and exercise. Long-acting preparations of divalproex or lithium, or taking SGAs before bed tend to decrease gastrointestinal upset. An endocrine consultation is needed to evaluate for hypothyroidism, which may or may not be related to lithium use.

Since the commencement of our algorithm project and the subsequent publication of our feasibility study (Pavuluri et al., 2004d), we have continued to update our strategies and tactics based on new information. Aripiprazole (Abilify) was added to the list of SGAs. The role of lamotrigine has been elevated. Atomoxetine was added as a second-line medication for comorbid ADHD. Clonidine has been shown to cause worsening of symptoms in a subgroup of patients with PBD, despite excellent short-term response for autonomic arousal.

We are closely monitoring this phenomenon. Consequently, we chose guanfacine (Tenex) (given the longer half-life compared to clonidine) or propranolol as an alternative for extreme hyperarousal that does not respond to mood stabilization. Given the recent review presenting equivocal evidence of trazodone's efficacy as a sleep medication (James and Mendelson, 2004), it was placed lower than melatonin, which had better data to support safety and efficacy in idiopathic insomnia (Smits et al., 2003), though it was not tested for sleep problems directly in PBD.

) integrates interpersonal psychotherapy principles with CBT for the child, parents and siblings (Pavuluri et al., 2004a). This intervention can also be exported to the child's school, if the family opts. It integrates the theoretical underpinnings of the phenomenology of PBD; the biological process of affect dysregulation; and the psychosocial burden placed on families. It also complements the medication management of the child.

Connecting and Enriching Community Resources

Given the multiple demands on the clinician's practice and restricted availability to take multiple supportive phone calls, it is necessary to arrange alternative and additional sources of support for the families of affected children. This is particularly effective if the support comes from families with similarly affected children. Families are taught how to advocate for their child. Reading materials are also made readily available. Many Web sites maintain a list of physicians that treat PBD and often provide feedback on a doctor's effectiveness; <www.bpkids.com> is particularly valuable resource for patients and their families.

Pediatric bipolar disorder affects the cognitive, behavioral and affective domains of a child's being. Affect dysregulation is the central feature. It is not clear that the juvenile-onset version of PBD is contiguous with adult BD. The primary goal of pharmacotherapy is mood stabilization, dealing with complex comorbid, residual, breakthrough and/or associated symptoms. It is imperative that any medication management be coupled with a meaningful holistic therapeutic approach that is practical and tailored to PBD.

Dr. Pavuluri is director of the Pediatric Mood Disorders Clinic and the Bipolar Research Program for Juvenile Research at the University of Illinois, Chicago (UIC).

Dr. Naylor is director of child psychiatry at UIC.

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Bipolar disorder in children is particularly difficult to treat. A treatment algorithm combining pharmacology with psychotherapy in order to get optimal results is presented.

Mani N. Pavuluri, MD, PhD

Articles

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