P. is a 6-year-old female who presented to a pediatric emergency room in Minneapolis for treatment of acute suicidality, manifested by repeated attempts to leap from the family’s 5-story window. This extreme behavior was the culmination of a two-day-long period of escalating activity, during which time both patient and patient’s biological mother experienced an episode of sleeplessness accompanied by marked irritability. While P.’s mother carried a diagnosis of bipolar I, the patient herself had been clinically assessed as having attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and depression.
Current medications included Adderal XR, 25 mg PO daily, clonidine, 50 mcg PO daily, and sertraline, 50 mg PO.
The patient had a social history significant for severe family discord. Her father had been jailed since P. was two and one half years old, with an anticipated release date in the upcoming month. P.’s 13-year-old sister was reported to have behavioral problems involving sporadic fits of anger leading to frequent absences from the household. It appeared from the initial interview that P.’s mother’s bipolar disorder was perhaps not being adequately controlled, as information-gathering was hindered by pressured speech and flight of ideas from the informant. She did, nonetheless, maintain current prescriptions for venlafaxine, sertraline, and clonazepam, though strict compliance with a medication regiment could not be assessed.
Research in pediatric bipolar (BP) disorder has flourished in the new millennium, thanks largely in part to several large-scale, prospective studies including 1995’s landmark NIMH-sponsored project, ‘Phenomenology and Course of Pediatric Bipolarity,’ performed by Dr. Barbara Geller and colleagues at the University of Washington, St.Louis. In the years prior, there existed substantial controversy over both the nature and diagnosibility of prepubertal and adolescent bipolar disorder, despite early observations by Kraepelin that 38% of his manic patients first noted symptoms before the age of 20 (Kraepelin 1921). Difficulties with extrapolating DSM-III and even DSM-IV criteria to the child and adolescent population, as well as dissimilarities between the expression of youth and adult pathology, obfuscated efforts at making clear diagnoses. While some of these uncertainties persist today, especially those regarding the neurobiological underpinnings of BP, clinicians do have at their disposal a substantial body of research that can help aide in the diagnosis and treatment of prepubertal and adolescent onset bipolar disorder.
Lifetime prevalence of bipolar disorder has been estimated in adolescents at 0.90-1.41% (Lewinsohn et al., 1995). Published studies on childhood BP prevalence are not available, but estimates range from 0.2-0.4% (Upadhyaya and Fields, 2004). When the patient is a first-degree relative of a bipolar sufferer, the likelihood of similar pathology is increased; research has demonstrated that, in the offspring of bipolar parents, 50% meet criteria for DSM-IV psychiatric disorders, with 14-50% of this group meeting criteria for bipolar I, II, or cyclothymia (Chang et al., 2000). Retrospective research also points to the frequency of early onset, including one study that found over half of its 494 adult BP patients had experienced prodromal symptoms such as mood lability or episodic depression prior to age 19, with 5% of those surveyed recalling symptoms occurring before age 5 (Kowatch and DelBello, 2003). Evidence abounds that some form of BP disorder can present in youth, however there is disagreement over the precise nature of the disease process. Is childhood BP a wholly separate entity from an analogous adult diagnoses? Is it a more severe form presenting in a subject more vulnerable to injury? Or is it a constellation of symptoms that, when present, provide clues to the likelihood of developing a psychiatric disorder later in life?
Pediatric BP differentiates from the adult form in terms of level of chronicity and rapidity of cycling. In one study of pediatric patients with DSM-IV BP, 83.3% of participants were identified as having “any rapid cycling,” defined as a) rapid: four or more episodes per year, b) ultra-rapid: episodes lasting a few days to a few weeks, or c) ultradian: cycling within a 24-hour period. 86.7% of the bipolar subjects reported mixed mania symptoms, rated when mania or hypomania overlapped in occurrence with major depression or dysthymia (Geller et al., 1998). By contrast, adults typically have fewer mixed episodes, with more discrete onsets and offsets (Geller and Luby, 1997). Those adults who share the mixed, rapid-cycling chronicity more consistently found in pediatric cases—less than 20% of adult-onset cases--show a tendency toward poorer treatment response as well as overall prognosis (McElroy et al., 1992). Lending power to the hypothesis that pediatric BP might lend itself to adult mixed-episode nosology is the observation that young patients have similarly poor outcomes. One prospective study found that, among early-onset subjects, only 65.2% recovered while 55.2% of these relapsed (Geller et al., 2002). The authors do, however, note that further research is needed to determine whether these young patients will continue to demonstrate the same pattern of features into adulthood, or revert to a more typical, discrete, episodic adult presentation.
Within the pediatric BP category, pre-pubertal and post-pubertal forms are distinguished by behavioral characteristics specific to age. Data from the Washington University NIMH study reveals hypersexuality occurring in 24.2% of prepubertal and 70.4% of postpubertal cases, increased people-seeking in 54.6% of prepubertal versus 85.2% of postpubertal subjects, and ADHD comorbidity found in 97.0% of prepubertal compared to 74.1% of postpubertal BP cases (Geller et al., 1998). In this study, all subjects had age of onset during the prepubertal years. The differences in symptomatology relative to age have implications for clinicians, as adult criterion for BP may not always be translatable to a young patient. Diagnostic instruments have been developed to address this issue, and will be discussed later in this paper.
The differential diagnosis for pediatric BP is distinct from that of the adult form as it includes as its primary “rule-out” attention-deficit disorder with hyperactivity (ADHD) rather than substance use disorders and schizophrenia. Further complicating diagnosis is the high frequency of ADHD comorbidity with pediatric BP, a prospect that demonstrates the unlikelihood of generating a pure BP diagnosis via a reductionistic process. In fact, children exhibiting manic symptoms are oftentimes identified as being hyperactive and distractible, leading to presumed ADHD assessment.
Many researchers have studied the psychiatric disorders that most often present with prepubertal mania. Comorbidities range from 75-87% with ADHD (using DSM-IV mania criteria) to 46-79% with oppositional defiant disorder in prepubertal BP patients (Tillman et al., 2003). Other work has found ADHD comorbid with BP in 57% of subjects who had mania onset in adolescence, and in only 13% of those studied with adult-onset BP (Sachs et al., 2000). Interestingly, Tillman’s study also found that the onset of ADHD preceded that of manic symptoms by an average of two years, raising the question of whether ADHD is possibly an early point in the trajectory towards full-blown bipolar disorder. One study has demonstrated that the opposite (bipolar is an early step in a continuum towards ADHD) is less likely, as it was demonstrated that 91% of children with mania or a history of mania met ADHD criteria while only 19% of subjects with a preexisting ADHD diagnosis also met criteria for mania (Wozniak et al., 1995). It remains to be seen what the exact nature of the relationship between the disorders is, whether ADHD is merely an early description of a preexisting vulnerability that later puts one at risk for BP, whether both are outward signs of pathology in neurologic processes involving attentional and emotional regulation (such as the cortico-limbic-striatal circuit), or whether the coincidence of BP and ADHD symptoms in childhood, with phasing out of the latter as maturation occurs, points to the existence of separate disease processes that happen to have similar phenotypic presentations.
After P. was stabilized and put on 1:1 observation, the medical team had the opportunity to discuss the patient’s medication management with her primary care professional, a local psychiatric nurse practitioner. It was discovered that the patient’s sertraline dose had been increased in the past 6 months from 25 mg PO qhs to 50 mg. P. had also had clonidine newly added to her regimen at that time, and had had no change to her 0.5 mg tab per day dosage since then. The patient had been on Adderal for over one year. A decision was made with the consulting psychiatrist at the inpatient hospital to discontinue the Adderal and clonidine immediately, and taper the sertraline for two days, with an immediate drop in dosage to 12.5 mg from 25 mg.
Anecdotal accounts of stimulant treatment for ADHD precipitating manic episodes in children may be available in the literature, but published studies dispute this assertion. Carlson and others studied the effect of methylphenidate on 6 to 12-year-old boys at risk for bipolar disorder, finding no evidence that the drug exacerbated or brought on new manic symptoms in subjects tested (Carlson et al., 2000). More widely available are research accounts of “manic switching” in pediatric patients treated with antidepressants, especially serotonergic agents. Biederman and colleagues found that serotonergic antidepressants, while effective in treating bipolar depression, significantly increased risk of mania relapse in pediatric patients (Biederman et al., 2000). Recent work with adult subjects suggests that manic switching concurrent with antidepressant use is lessened when the patient is also on a mood stabilizer. A study published in 2004 found that 81.3% of its adult bipolar patients treated with either SSRIs, tricyclics, buproprion, or other antidepressant agents experienced a new manic, hypomanic, or mixed episode within 8 weeks, while only 18.8% of those simultaneously taking a mood stabilizer such as divalproex, lithium, or carbamazepine had the same adverse sequelae (Ghaemi et al., 2004). Current recommendations from the National Institute of Mental Health include caution against the use of antidepressant in BP patients without the use of a mood stabilizer.
Combination therapy has been posed as an effective treatment for pediatric and adolescent BP patients. Kowatch and colleagues reported in 2003 that 80% of the 20 subjects requiring combination treatment (one or two mood stabilizers plus either a stimulant, atypical antipsychotic, or antidepressant) responded with a greater than 50% improvement in Young Mania Rating Scale assessment after experiencing a less positive response with monotherapy (Kowatch et al., 2003). Investigators recognized the need for addressing the comorbid ADHD that occurred in 28 of the study’s 35 total subjects, and found good results from addition of a stimulant only after the patient’s BP disorder was stabilized.
Other research has compared the use of multiple mood stabilizers in various presentations of pediatric and adolescent BP. Lithium has been discovered to be most effective for patients presenting in a euphoric, manic state (Geller el al., 1998; Kowatch et al., 2000; Kafantaris et al., 2003). For mixed-state presentations, divalproex sodium has been shown to be a more effective first-line treatment, with the addition of an atypical antipsychotic if psychosis is also present (DelBello et al., 2002; Delbello 2004). New research comparing the use of mood stabilizers to atypical antipsychotics is pending, however some benefits such as easier dosing and rapid onset of action have been ascribed to the atypicals. Side effects such as weight gain and changes in glucose metabolism still need to be studied in the pediatric population.
Clinicians have at their disposal a number of diagnostic instruments available for helping in the identification of pediatric and adolescent BP. Barbara Geller and her colleagues at Washington University in St. Louis recognized the need for prepubertal-specific criteria to be added to the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS), originally developed by Puig-Antich and Chambers in 1978. Called the WASH-U-KSADS, this assessment tool consists of a semi-structured interview in which symptoms are rated on a continuous severity scale by both parent as well as the pediatric patient in question (Geller et al., 1994). The WASH-U-KSADS includes specific questions about onset and offset of symptoms, important for the classification of BP youth who are frequently rapid-cyclers. In addition, the authors included an area for ADHD assessment, as well as age-specific criteria to help discern manic behavior or thinking. Level of grandiosity and elation are scrutinized, two mania-specific symptoms not addressed in the original K-SADS. The test has been demonstrated to be reliable by its developers, with 100% interrater reliability attained in a study that compared WASH-U-KSADS results with those of researchers blind to actual subject diagnoses (Geller et al., 2001).
Other instruments valuable
in the assessment of pediatric BP include the Young Mania Rating Scale and Child
Behavior Checklist, both of which have shown to be affective in a structured
interview setting. Biederman and colleagues found a 97% rate of agreement in
diagnoses between structured interview results that included Young scale scoring
and those made by independent, blinded, clinicians (Biederman et al., 2003).
Both the structured and semi-structured interview formats are helpful aides,
and effectiveness is largely determined by proficiency of the interviewer in
addition to the diagnostic instruments employed.
Pediatric bipolar is a relatively new area of study for researchers and clinicians alike, and understanding of the process may still be in its infantile stages. Nonetheless, enough has been elucidated to guide practitioners faced with the task of treating a young BP patient. Future research into neurobiological underpinnings of the disorder will help elaborate current knowledge about mode of presentation in symptoms in youth, comorbidities, and treatment options.
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