Bipolar disorders in children and adolescents

Original Article

Bipolar Disorders in Children and Adolescents Naomi A. Schapiro, RN, MS, CPNP

ABSTRACT In the past decade, 7 million children in the United States had a mental health problem, with higher rates of medication use, primary care visits, and specialty care visits than children without such problems. Children with bipolar disorders can present diagnostic and referral dilemmas for the primary care pediatric nurse practitioner, and frequently these children take multiple medications that interact with commonly used antibiotics, over-the-counter medications, and contraceptives. Diagnostic criteria for mania are controversial and coexisting attention deficit/hyperactivity disorder, conduct disorder, and anxiety disorders can complicate the diagnosis and treatment. The primary care pediatric nurse practitioner role includes referral, co-management, and advocacy for this vulnerable population. J Pediatr Health Care. (2005). 19, 131-141.

Naomi A. Schapiro is Associate Clinical Professor, Department of Family Health Care Nursing, University of California, San Francisco. Reprint requests: Naomi A. Schapiro, 2 Koret Way, Room N-411-Y, San Francisco, CA 94143-0606; e-mail: [email protected]. 0891-5245/$30.00 Copyright © 2005 by the National Association of Pediatric Nurse Practitioners. doi:10.1016/j.pedhc.2005.01.012

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Fifteen-year-old Sean was diagnosed with attention deficit/hyperactivity disorder (ADHD) at age 8 years and has always had behavioral issues. He has taken mixed amphetamine salts (Adderall) since he was age 10, with documented effectiveness in improving his attention and reducing his impulsive behavior. This year his grades have plummeted. Sean has become increasingly irritable and has been out of the house twice overnight with no explanation. Sean’s parents are concerned about substance abuse and are not sure if they should seek psychiatric care or drug counseling for him. There is a family history of “mood swings.” Marina is a 16-year-old girl you are seeing for an urgent appointment, whose history and physical examination are consistent with a sinus infection. Marina lets you know that she was hospitalized last month after “losing it and throwing stuff at my mom” and that she has been discharged with instructions to take three psychiatric medications. “I’m feeling better now so I don’t want to take so many drugs,” she says. Marina was prescribed low-dose oral contraceptives at her school-based health center and wants to know if you can refill her prescription. She is allergic to amoxicillin, having reacted with urticaria at age 8 years. Her current medications are: topiramate, 25 mg at bedtime; quetiapine, 25 mg at bedtime; sertraline, 100 mg daily in the morning; and 0.1 mg levonorgestrel/20 µg ethinyl estradiol (Alesse) daily. The “new morbidities” of pediatrics, including ADHD, behavioral disorders, depression, and adolescent risk behaviors, are becoming an increasingly important part of primary care (Melnyk, Brown, Jones, Kreipe, & Novak, 2003; Schor, 2004). According to Mental Health, United States, 2002, 7 million children ages 5 to 17 years had a mental health problem (Simpson, Scott, & Henderson, 2002). Almost 27% of chilMay/June 2005

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dren with mental health problems took some type of medication for more than 3 months, three times the rate of children without mental health problems, and they also used primary care and specialty medical services at higher rates (Simpson et al.). Forty-four percent of youth admitted to inpatient mental health services in 1997 had mood disorders (Pottick, Warner, Isaacs, Henderson, Milazzo-Sayre, et al., 2002). This article will look at the spectrum of mood disorders generally called bipolar disorder (BPD), giving an overview of definitions, etiology, overlapping conditions, current controversies, and treatment. Particular attention will be paid to presentation and co-management issues for the primary care pediatric nurse practitioner (PNP). Children with bipolar disorder can affect a primary care pediatric practice in several ways: Like Sean, children with ADHD often have coexisting conditions that surface later, such as conduct disorders, substance abuse, and mood disorders. Parents and adolescents may consult the NP in primary care, requesting referrals to specialists. At other times, patients like Marina who present for routine or acute care are taking multiple medications for psychiatric conditions that may have adverse interactions with commonly used antibiotics, over-the-counter medications, and hormonal contraceptives. DEFINITION AND DIAGNOSTIC CRITERIA According to the Diagnostic and Statistical Manual of Mental Disorders, Text Revision (DSM-IV-TR) (American Psychiatric Association, 2000), BPDs are characterized by severe fluctuations in mood, namely episodes of mania or hypomania alternating with periods of depression (see Box 1 and Box 2 for criteria for mania and for depression, respectively). In a manic episode, the mood disturbance is severe enough to cause significant impairment in daily activities and interpersonal relationships or to necessitate hospi132

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talization to prevent harm to self or others; there may be psychotic features to the symptoms. Whereas persons experiencing manic episodes typically exhibit euphoria and grandiosity (Weckerly, 2002), they also may present as irritable. In hypomanic states, the same behavioral criteria are used, but the impairment is not severe enough to necessitate hospitalization, and the individual may be able to continue academic or occupational activities. In mixed episodes, the individual exhibits symptoms of both mania and depression almost every day (American Psychiatric Association). Children can be diagnosed with bipolar I disorder if the constellation of symptoms includes manic or mixed episodes; the child may or may not have had a major depressive episode. Bipolar II disorder consists of episodes of major depression and at least one hypomanic episode. In cyclothymic disorder, individuals fluctuate rapidly between hypomanic and depressive symptoms but do not meet criteria for either full mania or major depression (American Psychiatric Association, 2000). Bipolar disorder not otherwise specified (BPD-NOS) can be used for disorders with bipolar features that do not meet criteria for the other aforementioned diagnoses. These criteria were developed primarily for adults and, according to the DSM-IV-TR (American Psychiatric Association, 2000), the average age of onset of the BPDs is late adolescence to young adulthood. Currently, recommendations of a National Institute of Mental Health (NIMH) expert consensus panel are to use the adult criteria to diagnose pediatric bipolar disorder as well (NIMH, 2001). However, the typical adult presentation of bipolar I disorder, consisting of discrete periods of both mania and depression interspersed with normal functioning, is not seen as frequently in pediatrics. Instead, symptoms in children seem to be characterized by a long-duration episode of rapid cycling and mixed mania (NIMH), with fluctua-

tions in mood occurring daily or more than once a day (Weckerly, 2002), and the NIMH roundtable encourages clinicians to use the BPD-NOS category as a “working diagnosis” for children with this presentation (NIMH, p. 871). MANIA IN CHILDREN AND ADOLESCENTS Melancholia and mania were two of the three forms of mental illness described by ancient Greek physicians (Glovinsky, 2002), and the connection between melancholia and mania was noted as early as the second century CE. Case reports connecting melancholy and mania were published in the 18th century, but it was not until the 19th century that European physicians began to describe a circular madness, or one that alternated between periods of mania and depression. Systematic studies of young children with mania started in the 1920s, although the prevailing belief was that pre-adolescent children did not have the higher level cognitive structures that were necessary to exhibit grandiose delusions (Glovinksy, 2002; Weller, Calvert, & Weller, 2003). During the 1970s, there were published reports of the use of lithium in young children, and Davis (1979) published a landmark paper that described hyperactivity and emotional upheavals in children without grandiosity or psychotic symptoms. Controversy over the prevalence and quality of mania in childhood continues to this day (Carlson, 1998; NIMH, 2001), primarily over age-appropriate descriptions of manic behavior and whether a child can be manic without grandiosity or elation. It can be difficult to distinguish between age-appropriate restlessness, the fidgeting of children with ADHD, and the purposeful busy activity of mania (Harrington & Myatt, 2003). Looking at another behavior, the rapid speech of a child with a language disorder or ADHD may not appear different from the “pressured speech” of mania. In children younger than 7 years with limited Journal of Pediatric Health Care

BOX 1. Criteria for Manic Episode A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary). B. During the period of mood disturbance, three or more of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree: 1. inflated self-esteem or grandiosity 2. decreased need for sleep 3. more talkative than usual or pressure to keep talking 4. flight of ideas or subjective experience that thoughts are racing 5. distractibility (ie, attention too easily drawn to unimportant or irrelevant internal stimuli) 6. increase in goal-directed activity (either socially, at work or school, or sexually or psychomotor agitation) 7. excessive involvement in pleasurable activities that have a high potential for painful consequences (eg, engaging in unrestrained buying sprees, sexual indiscretions or foolish business investments) C. The symptoms do not meet criteria for a Mixed Episode. D. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features. E. The symptoms are not due to the direct physiological effects of a substance (eg, a drug of abuse, a medication, or other treatment) or a general medical condition (eg, hyperthyroidism). Note: Manic-like episodes that are clearly caused by somatic antidepressant therapy (eg, medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of Bipolar I Disorder. Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Copyright 2000. American Psychiatric Association.

TABLE 1. Manic behaviors and overlapping diagnoses Behaviors

Elation Grandiosity Pressured speech Irritability Hostility Impulsivity Hypersexuality Distractibility High levels of motor activity Sleep disturbance

Mania

X X X X X X X X X X

Attention Deficit Hyperactivity Disorder

Conduct Disorder

Anxiety Disorders

X X X X

X

X X X X X X

X X X

Adapted from American Psychiatric Association, 2000; Kim & Miklowitz, 2002; Weckerly, 2002.

ability to test reality, grandiosity is difficult to confirm (Carlson, 1998). In addition, in young children the primary historian is the parent, and parents do not necessarily represent their children’s thought processes accurately (Tillman, Geller, Craney, Bolhofner, Williams, et al., 2004). According to some researchers (Biederman, Faraone, Mick, Wozniak, Chen, et al., 1996), irritability is a hallmark of pediatric mania, especially when presenting children have a coexisting diagnosis of ADHD. The irritability of manic children has Journal of Pediatric Health Care

been described as severe, persistent, and violent, often involving explosive outbursts of physical or verbal aggression (Weckerly, 2002), as in the case of Marina. Children whose primary symptoms include irritability and disruptive behavior may be diagnosed with ADHD and/or conduct disorder without adequate exploration of their moods (Kim & Miklowitz, 2002), resulting in underdiagnosis of BPD. However, irritability is also a symptom of many psychiatric disorders, including ADHD, depression,

anxiety disorders, and conduct disorder (Kim & Miklowitz, 2002; see Table 1). If irritable children can be labeled as manic without grandiosity or elation, then the possibility exists of overdiagnosis, as suggested by Kim and Miklowitz in reviewing longitudinal studies of adolescents with a BPD diagnosis and no recurrences in adulthood. PSYCHOTIC FEATURES: MANIA OR SCHIZOPHRENIA? Pediatric-onset bipolar disorder is associated with higher rates of psyMay/June 2005

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BOX 2. Criteria for Major Depressive Episode A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. Note: Do not include symptoms that are clearly due to a general medical conditions, or mood-incongruent delusions or hallucinations. 1. depressed mood most of the day, nearly every day, as indicated by either subjective report (eg, feels sad or empty) or observation made by others (eg, appears tearful). Note: In children and adolescents, can be irritable mood. 2. markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account of observation made by others 3. significant weight loss when not dieting or weight gain (eg, a change of more than 5% in body weight in a month), or decrease or increase in appetite nearly every day. Note: In children, failure to make expected weight gains 4. insomnia or hypersomnia nearly every day 5. psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down) 6. fatigue or loss of energy nearly every day 7. feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely guilt or self-reproach about being sick) 8. diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others) 9. recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide B. The symptoms do not meet the criteria for a Mixed Episode. C. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D. The symptoms are not due to the direct physiological effects of a substance (eg, a drug of abuse, a medication) or a general medical condition (eg, hypothyroidism). E. The symptoms are not better accounted for by Bereavement, ie, after the loss of a loved one, the symptoms persist for longer than 2 months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation. Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Copyright 2000. American Psychiatric Association.

chosis than is found in persons with a later onset of BPD (Pavuluri, Herbener, & Sweeney, 2004). Delusions congruent with mania such as grandiosity are more common in pediatric BPD than in schizophrenia, whereas hallucinations and loosening of associations are more common in pediatric schizophrenia. Pavuluri and colleagues suggest that a psychotic presentation in BPD is underrecognized in children or mistakenly thought to be related to schizophrenia. Diagnosing disturbances in reality testing requires a developmental approach: looking at the age-appropriateness of the delusion and the child’s realitytesting abilities, whether the child is acting on the thought, and any impairment in function caused by the delusion (Carlson, 1998). Some auditory hallucinations—such as hearing footsteps, knocking, or one’s name— 134

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occur in persons without a psychiatric disorder (Pavuluri, Herbener, et al.). DIAGNOSIS Given the clinical difficulties in the diagnosis and treatment of BPD, its evaluation and management are outside the scope of most primary care clinicians (Weckerly, 2002). When parents of a child like Sean consult the primary care PNP, the differential diagnosis is broad and there may be no one “red flag” behavior that would prompt a diagnosis of BPD. However, parental report of severe and prolonged temper tantrums, hyperactivity together with irritable and rapidly alternating moods, reckless and impulsive behavior, and a family history of mood disorders and/or substance abuse should prompt a referral for an evaluation for BPD (Muriel, Bostic, & Dolan, 2002; Weckerly).

While parents can be reliable historians of their child’s behavior, the PNP should screen the older child and adolescent directly and separately from the parent for symptoms of depression, either by in-depth questioning or by use of screening tools (Muriel et al., 2002). Muriel and colleagues recommend asking about feelings of guilt, worthlessness, anhedonia, and somatic symptoms, as well as thoughts about dying and more explicitly suicidal ideation or plans. Bright Futures in Practice: Mental Health, Part II- Toolkit (Jellinek, Patel, & Froehle, 2002) offers two screening tools free of charge: the more general Pediatric Symptom Checklist and the Center for Epidemiological Studies Depression Scale for Children (CES-DC). Other depression scales, such as the Children’s Depression Inventory (Kovacs, 1985) are available for purchase. Journal of Pediatric Health Care

BOX 3. Web resources for NPs Cytochrome P and drug-drug interactions

http://www.edhayes.com/startp450.html http://www.fda.gov/cder/consumerinfo/druginteractions.htm http://www.mhc.com/Cytochromes/index.html

BOX 4. Resources for families Books

Greene, R. W. (2001). The explosive child: A new approach for understanding and parenting easily frustrated, chronically inflexible children (2nd Ed.). New York: HarperCollins. Lederman, J., & Fink, C. (2003) The ups and downs of raising a bipolar child: A survival guide for parents. New York: Simon & Schuster. Papolos, D., & Papolos, J. (2002). The bipolar child: The definitive and reassuring guide to childhood’s most misunderstood disorder. New York: Broadway Books. Waltz, M. (2000). Bipolar disorders: A guide to helping children & adolescents. Sebastopol, CA: O’Reilly & Associates. Organizations/Web resources

Child and Adolescent Bipolar Foundation http://www.bpkids.org The Juvenile Bipolar Research Foundation http://www.bpchildresearch.org The National Alliance for the Mentally Ill (NAMI) http://www.nami.org

The Achenbach Child Behavior Checklist (CBCL), which has parent, teacher, and youth report forms, can be a cost-effective and time-effective tool in primary care and other clinical settings (Perrin & Stancin, 2002). In a meta-analysis of studies that used both the CBCL and structured diagnostic interviews, Mick, Biederman, Pandina, and Faraone (2003) found statistically significant increases in the Withdrawn, Anxious/Depressed, Thought Problems, Attention Problems, Delinquency, and Aggression clinical scales among children with BPD. However, others suggest that the CBCL has limited ability to distinguish between BPD and other disruptive behavior disorders (Kahana, Youngstrom, Findling, & Calabrese, 2003). Mick and colleagues suggest that the concordance of elevated scales across research studies support the use of the CBCL for screening but not definitive diagnosis. Currently there is a lack of consistency across research groups Journal of Pediatric Health Care

about diagnostic criteria and assessment methods in pediatric BPD, which can inhibit efforts at developing scientific and therapeutic advancements (Mick et al., 2003). Researchers and clinicians in pediatric psychiatry clinics have used variations of the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age children (KiddieSADS-MRS, WASH-U-KSADS, or Kiddie-SADS-E), sometimes adding questions for mania (Axelson, Birnaher, Brent, Wassick, Hoover, et al., 2003; Geller, Williams, Zimerman, Frazier, Beringer, et al., 1998; Wozniak, Monuteaux, Richards, Lail, Faraone, et al., 2003). Wozniak and colleagues found a convergence of structured diagnostic interview and clinical evaluations in 67 of 69 youths studied. COEXISTING CONDITIONS The main diagnostic dilemmas in mood disorders involve distinguishing BPD from unipolar depression

or anxiety disorders, ADHD, and/or conduct disorder (Carlson, 1998). An additional quandary is whether the child has BPD only or has BPD in addition to coexisting conditions. The significance of these overlapping diagnoses will be clearer in the discussion of treatment below, because medications commonly used to treat anxiety disorders may precipitate manic episodes in children with undiagnosed BPD, and antiepileptic drugs are sometimes used as mood stabilizers. Between 30% and 50% of children with anxiety disorders also have a depressive disorder, either unipolar or bipolar (Varley & Smith, 2003). In a study of 2025 youths referred to an anxiety and mood disorders clinic, 19% of children with panic disorder also had BPD (Birmaher, Kennah, Brent, Ehmann, Bridge, et al., 2002). In one Italian study of children and adolescents at a tertiary care psychiatric center, about 45% of youths with diagnoses of either obsessive compulsive disorder or BPD showed a lifetime history of comorbidity (Masi, Perugi, Toni, Millepiedi, Mucci, et al., 2004). Up to 40% of hospitalized manic adolescents in one study had a substance use disorder (West, Strakowski, Sax, McElroy, Keck, et al., 1996). A preliminary survey of persons with epilepsy found that 8% had symptoms consistent with bipolar spectrum (Barry, 2003), and the author speculates that interictal mania may be more prevalent. Attention-Deficit Hyperactivity Disorder Clinical descriptions and diagnostic criteria for ADHD have changed over time, from the hyperkinetic child of the 1970s in whom emotional variability was a hallmark (Carlson, 1998) to the current definition of the DSM-IV-TR, which focuses entirely on inattention and hyperactivity/impulsivity (American Psychiatric Association, 2000). Kim and Miklowitz (2002) found that, depending on the studies they reviewed, 57% to 98% of children with mania also had a diagMay/June 2005

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TABLE 2. Medications—common mood stabilizers Medication/Class

Major adverse effects

Monitoring

Metabolic pathways

Lithium

Weight gain, sedation, rash, tremors, hypothyroid, polyuria, GI disturbance, low margin

Every 3-4 days during induction, then less frequently

90% eliminated through kidneys

Valproic acid (AED)

Hemorrhagic pancreatitis, Liver enzymes, bilirubin hepatic failure, hyperamserum ammonia, monemic encephalopathy, CBC thrombocytopenia, drowsiness, confusion, weight gain, GI distress

Carbamazepine (AED, Rash, Stevens-Johnson enzyme-inducing) syndrome, blood dyscrasias, cardiac arrythmias, sedation, dizziness, GI distress, weight gain Risperidone (atypical Weight gain, amenorrhea, antipsychotic) galactorrhea, dizziness, restlessness/somnolence, prolonged QT interval, tardive dyskinesia, neuroleptic malignant syndrome, rare liver toxicity

CBC with platelet count, liver functions, serum level

ECG, weight, BP, liver functions

Drug-drug/drug-food interactions

Diuretics, indomethacin, NSAIDS, Cox-2 inhibitors, ACE inhibitors, metronida zole, phenytoin Primarily through liver, Phenobarbitol, zidovudine, faster with polypharmacy amitryptiline, nortryptiline, and age <10 y lamotrigine, phenytoin CYP2C19 substrate, CYP2C9 and CYP2D6 inhibitor, weak CYP3A3/4 inhibitor Primarily through liver Clarithromycin, erythromycin, CYP2C8 and CYP3A3/4 fluoxetine, oral contraceptives, substrate, CYP1A2, cimetidine, ketoconazole, CYP2C, CYP3A3/4 benzodiazepines, antileuinducer kemic drugs, grapefruit juice CYP2D6, CYP 3A3/4 Carbamazepine, fluoxetine substrate; weak antihypertensive agents, CYP2D6 inhibitor, valproic acid

ACE, angiotensin-converting enzyme; AED, antiepileptic drug; BP, blood pressure; CBC, complete blood cell count; ECG, electrocardiogram; GI, gastrointestinal; NSAIDS, nonsteroidal anti-inflammatory drugs. Data from Drugdex (http://www.micromedex.com/, retrieved 9/26/04), Hatcher et al., 2003; Kusumakar et al., 2002; Taketomo et al., 2003.

nosis of ADHD, while 20% to 23% of children with ADHD also had a diagnosis of bipolar disorder. Faraone and colleagues suggest two different models to explanation this overlap. In one model, the combination of ADHD with BPD represents a distinct subtype, with higher rates of both ADHD and early onset BPD in the relatives of children with both diagnoses, compared with children with ADHD alone and with children who have no mental health diagnoses (Faraone, Biederman, Mennin, Wozniak, & Spencer, 1997). Another model posits that ADHD is a developmental marker for early-childhood onset BPD, with higher rates of ADHD noted among children with earlier appearance of manic symptoms (Faraone, Biederman, Wozniak, Mundy, Mennin, et al., 1997). Conduct Disorder The DSM-IV-TR defines conduct disorder as “a repetitive and persistent pattern of behavior in which the 136

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basic rights of others or major ageappropriate societal norms or rules are violated” (American Psychiatric Association, 2000, p. 93). Irritability in manic children is often violent, similar to the irritability in conduct disorder (Kim & Miklowitz, 2002; Weckerly, 2002). However, one distinguishing clinical characteristic is the often rapid onset of irritable, impulsive outbursts in BPD, contrasting with a lengthy prodromal period in conduct disorder, progressing from less severe to more severe rulebreaking. Two other characteristics specific to BPD are the episodic nature of the violent outburst, as well as the guilt and remorse the child generally exhibits when the outburst is over (Kusumakar, Lazier, MacMaster, & Santor, 2002). In one study of children referred to a psychopharmacology clinic in Boston, 41% of children with mania met criteria for conduct disorder, and 40% of children with conduct disorder had symptoms of mania (Biederman,

Faraone, Chu, & Wozniak, 1999). Other symptoms common to both disorders are inappropriate sexual behavior, disinhibited social interactions, and displays of poor judgment. More empiric studies are required to distinguish age of onset, quality of mood disturbance, and the clinical course of children with mania alone, conduct disorder alone, and both diagnoses (Kim & Miklowitz, 2002). ETIOLOGY AND PATHOPHYSIOLOGY Although the specific genes moderating the expression of BPD have not been confirmed, studies of adult monozygotic twins have found that 60% of the variance in bipolar disorder was attributable to genetic factors (Faraone, Glatt & Tsuang, 2003). Adoption studies reviewed by the same authors showed an increased prevalence of BPD in the biologic, but not in the adoptive, parents of adults with BPD. Studies of pediatric-onset Journal of Pediatric Health Care

TABLE 3. Marina’s medications Medication/Class

Major adverse effects

Monitoring

Metabolic pathways

Drug-drug/drug-food interactions

Topiramate (AED)

Ocular syndrome (glaucoma, myopia), ataxia, fatigue, somnolence, memory difficulties, paresthesia, tremor, nephrolithiasis Sedation, dry mouth, GI distress, weight gain, tachycardia, neuroleptic malignant syndrome GI distress, weight loss, mania/hypomania, sexual dysfunction, dizziness, headache, platelet abnormalities, ↓ uric acid ↑ blood clotting, fluid retention, edema, fatigue, mood changes, breast tenderness, migraine headache, gall bladder disease, benign hepatomas

Renal function

70% through kidneys, minor amounts through CYP2C19 substrate and inhibitor

Phenytoin, carbamazepine, valproic acid, oral contraceptives, digoxin, alcohol

CBC, liver function tests, ECG, serum prolactin, chemistries, eye exams

70% excreted through kidneys, extensive first pass through liver, CYP3A3/4

Carbamazepine, ketoconazole, rifampin, risperidone, erythromycin

Weight and growth, uric acid, CBC, liver functions

Liver, significant first pass effect, CYP3A3/4 and CYP2D6 substrates, CYP2C9, CYP2C19, CYP3A3/4 inhibitor Liver, significant first pass effect

MAO inhibitors, tricyclic antidepressants, tolbutamide, diazepam, cimetidine, erythromycin, buspirone, pi mozide, amphetamines, sumatriptan, grapefruit juice

Quetiapine (atypical antipsychotic)

Sertraline (SSRI)

Ethinyl estradiol and levonorgestrel (oral contraceptive)

Symptoms

Carbamazepine, topiramate, rifampin, ketoconazole, oral antibiotics (controversial)

AED, Antiepileptic drug; CBC, complete blood cell count; ECG, electrocardiogram; GI, gastrointestinal; MAO, monoamine oxidase; SSRI, selective serotonin reuptake inhibitors. Data from Drugdex (http://www.micromedex.com/, retrieved 9/26/04), Hatcher et al., 2003; Kusumakar et al., 2002; Taketomo et al., 2003.

BPD seem to indicate that the earlier the onset, the stronger the association with increased prevalence among relatives, but there is a paucity of twin and adoption studies of pediatric probands (Faraone et al., 2003). Studies of the children (≤21 years) of bipolar parents show increased incidence of mood, anxiety, and disruptive behavior disorders (DelBello & Geller, 2001). Genetic researchers are also exploring the possibility of “anticipation” in BPD, in which illness severity increases in subsequent generations (Kusumakar et al., 2002). Researchers suggest that BPD is characterized by severe fluctuations in state, encompassing not just mood, but also changes in behavior, cognition, and level of arousal, such as the decreased need for sleep and grandiosity present during manic episodes, and generalized impairment in problem-solving (Leibenluft, Charney, & Pine, 2003; Pavuluri, Journal of Pediatric Health Care

Graczyk, Henry, Carbray, Heidenreich, et al., 2004). Brain structures implicated include the frontal and prefrontal cortex, the amygdala, hippocampus, and basal ganglia (Leibenluft et al.) Functional magnetic resonance imaging studies show abnormalities in adults with BPD such as asymmetry in the prefrontal cortex (Kusumakar et al., 2002; Leibenluft et al.), but these results have not been duplicated in adolescents. Practical obstacles to imaging manic children, as well as the ongoing development of the prefrontal cortex during adolescence (Pine, 2000) add to the challenges of future research. PHARMACOLOGIC TREATMENT Pharmacotherapy is the mainstay of treatment for children, as well as adults, with BPD (Weckerly, 2002). As with many psychiatric disorders, treatment for children has been extrapolated from successful

trials of medications in adults. The only placebo-controlled trials in juvenile BPD have demonstrated the efficacy of lithium in adolescents with comorbid substance abuse, and the efficacy of quetiapine as adjunctive to valproate (Bhangoo, Lowe, Myers, Treland, Curran, et al., 2003). Lithium carbonate, the medication in longest use for bipolar disorder, and valproic acid, originally used for seizure disorder, are relatively equal in effectiveness as short-term monotherapy (Kusumakar et al., 2002), each showing significant reductions in mania and improvement in global functioning for half the children who take them in randomized clinical trials (Kowatch, Sethuraman, Hume, Kromelis, & Weinberg, 2003). Kowatch and colleagues found carbamazepine, another antiepileptic drug, to be slightly less effective as a single medication. However, up to half of children treated with mood May/June 2005

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stabilizers do not respond to their initial therapy, requiring either a switch to another mood stabilizer, use of two mood stabilizers, or an added antipsychotic medication, and even children who do respond initially may need to be switched during the first 6 months of treatment (Kowatch et al.; see Table 2, Common Mood Stabilizers). Despite the lack of controlled trials showing efficacy in children, community samples show that children are taking a variety of mood stabilizers, antipsychotics, and selective serotonin reuptake inhibitors (Bhangoo et al., 2003). In a telephone survey of interested families followed by community psychiatrists, children with bipolar disorder were taking a mean of 3.4 medications, with the number of different medications ranging from 0 to over 5. Ninety-eight percent of the children had had a trial of a mood stabilizer/antiepileptic drug, with the most common being valproic acid, lithium, and gabapentin. Seventyseven percent of the children had taken an antipsychotic drug, most commonly risperidone, olanzapine, and quetiapine (Bhangoo et al.). Despite lithium carbonate’s long track record and proven efficacy, adolescents may not tolerate this medication as well as valproic acid or others (Kusumakar et al., 2002). Lithium has a low margin of safety and can be lethal in overdose, making its use problematic in uncooperative children or chaotic families where compliance and monitoring are issues (Kusumakar et al.). Lithium can cause weight gain and nausea or diarrhea, sedation, tremor, hypothyroidism, and polyuria. Lithium is primarily eliminated by the kidney, and blood levels must be monitored every 3 to 4 days during induction of the medication (Taketomo, Hodding, & Kraus, 2003). Valproic acid also causes significant weight gain and may have an association with polycystic ovary syndrome in young women who are taking it (Kusumakar et al., 2002). Valproic acid is eliminated by the 138

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liver, and there are rare reports of liver toxicity, primarily in very young children taking multiple medications. Valproic acid can cause transient thrombocytopenia, and thus periodic blood counts are indicated (Taketomo et al., 2003). In addition to weight gain and sedation, carbamazepine can cause blood dyscrasias and severe hypersensitivity (Taketomo et al.). Atypical or second-generation antipsychotics, such as olanzapine, risperidone, and quetiapine, show lower rates of extra pyramidal side effects and tardive dyskinesia than do traditional antipsychotics, such as thorazine or haloperidol (Findling & McNamara, 2004). Atypical antipsychotics have shown promise in the treatment of adults with bipolar disorder (Mitchell & Malhi, 2002). As noted by Bhangoo and colleagues (2003), the majority of surveyed children with BPD have been prescribed an antipsychotic drug, despite the lack of controlled trials in children and adolescents. However, open trials of risperidone and olanzapine and one double-blind study of quetiapine added to valproic acid have shown efficacy in decreasing manic symptoms and improving sleep patterns (Findling & McNamara). Pharamacologic Treatment of ADHD in Children With BPD Given the high comorbidity of BPD with ADHD and the usual appearance of symptoms consistent with BPD after the diagnosis of ADHD, there has been some controversy regarding the use of stimulants in children with mood disorders, particularly concerns about worsening of mania with stimulants (Bhangoo et al., 2003) and lack of efficacy (Kusumakar et al., 2002). Carlson, Loney, Salisbury, Kramer, and Arthur (2000), reporting on a longitudinal study of boys with ADHD considered to be at risk for BPD, found that boys who eventually were diagnosed with BPD did not respond to methylphenidate differently than did boys without a BPD diagnosis, either in dosage, change of medica-

tion, associated symptoms, or a precipitation of manic or hypomanic symptoms. However, other studies, including case reports, indicate that use of methylphenidate is associated with new or increased manic symptoms (State, Altshuler, & Frye, 2002). Because some children spontaneously switch from depressed or euthymic to manic states, it is difficult to attribute causality in any particular child (State et al.). Pharmacologic Treatment of Depression in Children With BPD Some children initially present as depressed, rather than manic, or have a mixed picture (such as BPD II) with both depressed and hypomanic symptoms that are not initially assessed as being clinically significant (Cicero, El-Mallakh, Holman, & Robertson, 2003). These children may be diagnosed as having unipolar depression and started on selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine or sertraline. In reviewing the research on SSRIs and mania, Cicero and colleagues noted that numerous adult studies associate SSRI treatment with shifts to mania and a more rapid rate of switching than would be expected without medication. In a retrospective chart review, they found that prior SSRI use was associated with a younger age of diagnosis of BPD. A recent review, through a database, of the medication histories of 7 million privately insured persons ages 5 to 29 years found that 5.4% converted into their first known manic episode during antidepressant therapy (Martin, Young, Leckman, Mukonoweshuro, Rosenheck, et al., 2004), and that 10- to 14-yearolds seemed to be most vulnerable to this conversion. Even when BPD I or II is the recognized diagnosis, lithium, valproic acid, and carbamazepine have limited effect in treating depressive symptoms and an SSRI may be prescribed along with a mood stabilizer, although evidence for or against the Journal of Pediatric Health Care

effectiveness of this combination has not yet been accumulated (Kusumakar et al., 2002). In their study of community treatment of BPD, Bhangoo and associates (2003) found that 52% of the children in their study experienced activating adverse effects from SSRIs, although they were not able to control for concurrent mood stabilizer use. The Role of the Primary Care PNP in Prescribing Medications to Children With BPD The challenges of providing primary care to children with BPD include monitoring multiple medications and avoiding adverse drugdrug interactions, as exemplified in the case of Marina. Like many children in the community, Marina is taking three medications in a combination that has not yet been validated by the research literature: an antipsychotic (quetiapine), a mood stabilizer/AED (topiramate) and an SSRI (sertraline) (Bhangoo et al., 2003). Table 3 shows potential drug-drug interactions for Marina’s medications, and Box 3 provides Web resources for more information on drug interactions. For a youth who is allergic to amoxicillin, macrolides are a reasonable choice for sinusitis, but erythromycin and clarithromycin may interact with quetiapine to prolong the QTc interval (Taketomo et al., 2003). There are several choices among the cephalosporin antibiotics, such as cefuroxime axetil, cefpodoxime, cefdinir, and loracarbef, which do not interact with any of Marina’s medications, but there is some risk of cross-reactivity to cephalosporins in a child who is allergic to amoxicillin (Taketomo et al.). Topiramate, like most antiepileptic drugs, results in increased clearance and decreased serum concentrations of estrogen, rendering low-dose oral contraceptives ineffective (Hatcher, Nelson, Zieman, Darney, Creinin, et al., 2003; Taketomo et al., 2003) Because hypersexuality and increased impulsivity are both common in manic perJournal of Pediatric Health Care

sons (DelBello & Grcevich, 2004) and because most mood stabilizers have teratogenic risks (Kusumakar et al., 2002), it is particularly important for Marina’s PNP to ensure that she is using a hormonal contraceptive that is effective in combination with her medication. Hatcher and colleagues offer three alternatives: (a) a high-dose combined oral contraceptive with 50 µg of estrogen; (b) a 35 µg pill, either given continuously without pill-free intervals or two cycles without a pill-free interval; or (c) depot medroxyprogesterone injections every 12 weeks. NONPHARMACOLOGIC TREATMENT The goals of a therapeutic relationship for the child with BPD are to (a) recognize symptoms and dysfunction early so that effective intervention can control symptoms, (b) prevent deterioration, and (c) promote healthy development and optimal functioning (Kusumakar et al., 2002). Building such a relationship is no easy task: older children and adolescents may be resistant to treatment, and families may have been drained by both the child’s symptoms and by the “often protracted pathway into appropriate care” (Kusumakar et al., p. 117). Several studies have shown that high levels of critical, hostile, or emotionally overinvolved attitudes in parents or spouses (also known as high expressed emotion) are associated with higher rates of relapse and poor symptomatic outcomes in adults with BPD, confirming outcomes previously associated with schizophrenia (Miklowitz, Simoneau, George, Richards, Kalbag, et al., 2000). Multifamily psychoeducation groups for preadolescent children with BPD have been shown to be effective in one randomized controlled trial (Fristad, Gavazzi, & MackinawKoons, 2003). Treatment children report significant gains in social support from their parents and peers, and treatment families report increased knowledge and ability to obtain appropriate services. An open

trial of child-focused and family-focused cognitive behavioral therapy has been found to significantly decrease symptoms in children ages 5 to 17 years who are taking stabilizing medications, including children with coexisting conditions such as ADHD (Pavuluri, Graczyk, et al., 2004). Unfortunately, many families lack the economic resources or insurance coverage to access comprehensive mental health services for their children (Melnyk et al., 2003; Simpson et al., 2002). Respected researchers in Missouri (Geller et al., 1998) note as a limitation to their studies the lack of psychiatric services for publicly insured or uninsured children. In a nationwide review of private health insurance, Fox, McManus and Reichman (2003) found that only 2% of plans nationwide would cover all recommended services for an adolescent with BPD and substance abuse, and many plans would specifically exclude the family groups found to be effective by Fristad and colleagues (2003). Sean’s parents are likely to find coverage for at least diagnosis and initial treatment, whether he turns out to have a mood disorder, substance abuse or both, and a dual diagnosis might increase his eligibility for services (Fox et al.). But Marina, who is already considering discontinuing some of her medications, may not have the coverage for either long-term psychiatric follow-up or a psychoeducational group involving her family. LONG-TERM PROGNOSIS Adults with bipolar I disorder had episodes of mania lasting, on average, 9 weeks and were symptomatic for less than half the time, in one 12year longitudinal study (Judd, Aksiskal, Schettler, Endicott, Maser, et al., 2002). In contrast, prepubertal and early adolescent children with bipolar I disorder, in a 4-year study, had manic episodes lasting more than a year, with relapse rates up to 70% (Geller et al., 2004). Psychotic symptoms were found to be an indicator of poor functioning between episodes and poor recovery (Geller May/June 2005

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et al., 2004). Children and adults with bipolar I disorder might be expected to have a severe course, and longitudinal studies of bipolar II disorder and BPD-NOS are indicated. Up to 25% of children and adults with BPD attempt suicide, especially during depressive episodes (Dalton, Cate-Carter, Mundo, Parikh, & Kennedy, 2003), and persons with substance abuse or rapid cycling are at increased risk. Poor adjustment in childhood or adolescence has been associated with alcohol and drug use (Goldberg & Ernst, 2004). Papolos and Papolos (2002), summarizing the concerns of parents of children with BPD children posted on a listserv over a 1-year period, note that parents want more outcomes research, more outreach and education for families struggling to help their children, more inpatient and outpatient mental health services, and screening for depression in schools. Parents particularly expressed concern that their children with periodic explosive outbursts might end up in adolescent detention centers instead of psychiatric hospitals. Their concerns are supported by a U.S. Government Accounting Office (GAO) report that children are being placed in both the child welfare and juvenile justice systems solely to obtain needed mental health services (2003). THE PNP AS ADVOCATE In addition to providing families with appropriate mental health referrals and helping to monitor the effects and interactions of psychiatric medications, the primary care PNP will also be asked to advocate for children with serious mental health problems, including BPD (see Box 4 for family resources.) This advocacy may take the form of negotiating with an individual child’s health insurance for more comprehensive services or advocating with the child’s school for appropriate placement and services. Advocacy is also important on the community and statewide level, or in national campaigns such as KySS (Melnyk et al., 2003) to improve ac140

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cess to mental health treatment and the quality of available services. Although much remains to be known about optimal diagnosis and treatment of BPD, primary care PNPs can help improve outcomes for children with BPD through early diagnosis and coordination of care. REFERENCES American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed., text revision). Washington, D. C.: Author. Axelson, D., Birnaher, B. J., Brent, D., Wassick, S., Hoover, C., Bridge, J., et al. (2003). A preliminary study of the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children Mania Rating Scale for children and adolescents. Journal of Child and Adolescent Psychopharmacology, 13, 463-470. Barry, J. J. (2003). The recognition and management of mood disorders as a comorbidity of epilepsy. Epilepsia, 44(S4), 30-40. Bhangoo, R., Lowe, C. H., Myers, F. S., Treland, J., Curran, J., Towbin, K. E., et al. (2003). Medication use in children and adolescents treated in the community for bipolar disorder. Journal of Child and Adolescent Psychopharmacology, 13, 515-522. Biederman, J., Faraone, S. V., Chu, M. P., & Wozniak, J. (1999). Further evidence of a bidirectional overlap between juvenile mania and conduct disorder in children. Journal of the American Academy of Child and Adolescent Psychiatry, 38, 468-476. Biederman, J., Faraone, S., Mick, E., Wozniak, J., Chen, L., Ouellete, C., et al. (1996). Attention-deficit hyperactivity disorder and juvenile mania: An overlooked comorbidity? Journal of the American Academy of Child and Adolescent Psychiatry, 35, 997-1008. Birmaher, B., Kennah, A., Brent, D., Ehmann, M., Bridge, J., & Axelson, D. (2002). Is bipolar disorder specifically associated with panic disorder in youths? Journal of Clinical Psychiatry, 63, 414-419. Carlson, G. A. (1998). Mania and ADHD: Comorbidity or confusion. Journal of Affective Disorders, 51,177-187. Carlson, G. A., Loney, J., Salisbury, H., Kramer, J. R., & Arthur, C. (2000). Stimulant treatment in young boys with symptoms suggesting childhood mania: A report from a longitudinal study. Journal of Child and Adolescent Psychopharmacology, 10, 175-184. Cicero, D., El-Mallakh, R. S., Holman, J., & Robertson, J. (2003). Antidepressant exposure in bipolar children. Psychiatry, 66, 317-322. Dalton, E. J., Cate-Carter, T. D., Mundo, E., Parikh, S. V., & Kennedy, J. L. (2003). Suicide risk in bipolar patients: The role

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