Bipolar disorder in children is particularly difficult to treat. A treatment algorithm combining pharmacology with psychotherapy in order to get optimal results is presented.
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).
Defining the Targets of Treatment
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 DSM-IV-TR symptoms. A score of >15 (out of 63) indicates a 92% chance of having the diagnosis. However, it is not a diagnostic tool.
Principles of Medication Algorithm
Basic principles of this algorithm model consist of prescription hygiene, mood stabilization, addressing breakthrough symptoms and problem solving.
Prescription hygiene. 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.
Mood stabilization. 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.
In Table 1 and Table 2, 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 ).
Addressing breakthrough symptoms. 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.
Depression. 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.
Psychosis. The SGAs must be added to the regimen, working down the list as indicated in Table 2 (Pavuluri et al., 2004d, 2004e).
Persistent aggression. Switch to SGA monotherapy if mild aggression is present. In moderate to severe presentations, a combination of mood stabilizer and SGA is used (Table 1 and Table 2). 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.
Treatment resistance. 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.
Sleep difficulties. 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).
Problem solving. 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. 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.
Adverse events. 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.
RAINBOW Therapy Intervention
RAINBOW therapy (Figure) 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.
Balon R (1994), Sleep terror disorder and insomnia treated with trazodone: a case report. Ann Clin Psychiatry 6(3):161-163.
Bernstein GA, Garfinkel BD, Borchardt CM (1990), Comparative studies of pharmacotherapy for school refusal. J Am Acad Child Adolesc Psychiatry 29(5):773-781.
Biederman J, Mick E, Spencer T et al. (2000), Therapeutic dilemmas in the pharmacotherapy of bipolar depression in the young. J Child Adolesc Psychopharmacol 10(3):185-192.
Birmaher B, Axelson DA, Monk K et al. (2003), Fluoxetine for the treatment of childhood anxiety disorders. J Am Acad Child Adolesc Psychiatry 42(4):415-423.
Black B, Uhde TW (1994), Treatment of elective mutism with fluoxetine: a double-blind, placebo-controlled study. J Am Acad Child Adolesc Psychiatry 33(7):1000-1006 [see comment].
Bowden CL (2002), Lamotrigine in the treatment of bipolar disorder. [Published erratum Expert Opin Clin Pharmacother 3(11):1683.] Expert Opin Pharmacother 3(10):1513-1519.
Calabrese JR, Suppes T, Bowden C et al. (2000), A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 Study Group. J Clin Psychiatry 61(11):841-850.
Carlson GA, Bromet EJ, Sievers S (2000), Phenomenology and outcome of subjects with early- and adult-onset psychotic mania. Am J Psychiatry 157(2):213-219.
Carlson GA, Kelly KL (1998), Manic symptoms in psychiatrically hospitalized children-what do they mean? J Affect Disord 51(2):123-135.
DelBello M, Kowatch R, Adler C, Strakowski S (2004), Controlled trial of quetiapine versus divalproex for the treatment of pediatric bipolar disorder. Presented at the 51st Annual Meeting of the American Academy of Child and Adolescent Psychiatry. Washington, D.C.; Oct. 22.
DelBello MP, Schwiers ML, Rosenberg HL, Strakowski SM (2002), A double-blind, randomized, placebo-controlled study of quetiapine as adjunctive treatment for adolescent mania. J Am Acad Child Adolesc Psychiatry 41(10):1216-1223.
DelBello MP, Soutullo CA, Hendricks W et al. (2001), Prior stimulant treatment in adolescents with bipolar disorder: association with age at onset. Bipolar Disord 3(2):53-57.
Faraone SV, Glatt SJ, Tsuang MT (2003), The genetics of pediatric-onset bipolar disorder. Biol Psychiatry 53(11):970-977.
Frazier JA, Biederman J, Tohen M et al. (2001), A prospective open-label treatment trial of olanzapine monotherapy in children and adolescents with bipolar disorder. J Child Adolesc Psychopharmacol 11(3):239-250.
Geller B, Sun K, Zimerman B et al. (1995), Complex and rapid-cycling in bipolar children and adolescents: a preliminary study. J Affect Disord 34(4):259-268.
Geller B, Tillman R, Craney JL, Bolhofner K (2004), Four-year prospective outcome and natural history of mania in children with a prepubertal and early adolescent bipolar disorder phenotype. Arch Gen Psychiatry 61(5):459-467 [see comments].
Graae F, Milner J, Rizzotto L, Klein RG (1994), Clonazepam in childhood anxiety disorders. J Am Acad Child Adolesc Psychiatry 33(3):372-376.
Gustavson LE, Boellner SW, Granneman GR et al. (1997), A single-dose study to define tiagabine pharmacokinetics in pediatric patients with complex partial seizures. Neurology 48(4):1032-1037.
James SP, Mendelson WB (2004), The use of trazodone as a hypnotic: a critical review. J Clin Psychiatry 65(6):752-755.
Kafantaris V, Coletti DJ, Dicker R et al. (2001a), Adjunctive antipsychotic treatment of adolescents with bipolar psychosis. J Am Acad Child Adolesc Psychiatry 40(12):1448-1456.
Kafantaris V, Dicker R, Coletti DJ, Kane JM (2001b), Adjunctive antipsychotic treatment is necessary for adolescents with psychotic mania. J Child Adolesc Psychopharmacol 11(4):409-413.
Kowatch RA, Sethuraman G, Hume JH et al. (2003), Combination pharmacotherapy in children and adolescents with bipolar disorder. Biol Psychiatry 53(11):978-984.
Mathias S, Wetter TC, Steiger A, Lancel M (2001), The GABA uptake inhibitor tiagabine promotes slow wave sleep in normal elderly subjects. Neurobiol Aging 22(2):247-253.
Mota-Castillo M, Torruella A, Engels B et al. (2001), Valproate in very young children: an open case series with a brief follow-up. J Affect Disord 67(1-3):193-197.
Pavuluri MN, Graczyk PA, Henry DB et al. (2004a), Child- and family-focused cognitive-behavioral therapy for pediatric bipolar disorder: development and preliminary results. J Am Acad Child Adolesc Psychiatry 43(5):528-537.
Pavuluri MN, Henry DB, Carbray JA, Birmaher B (2004b), Child Mania Rating Scale (CMRS): development, reliability and validity. Biol Psychiatry 55(suppl):845S.
Pavuluri MN, Henry DB, Carbray JA et al. (2004c), Open-label prospective trial of risperidone in combination with lithium or divalproex sodium in pediatric mania. J Affect Disord 82(suppl 1):S103-S111.
Pavuluri MN, Henry DB, Devineni B et al. (2004d), A pharmacotherapy algorithm for stabilization and maintenance of pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry 43(7):859-867.
Pavuluri MN, Herbener ES, Sweeney JA (2004e), Psychotic features in pediatric bipolar disorder. J Affect Disord 80(1):19-28.
Pavuluri MN, Janicak PG (2004), Handbook of Psychopharmacotherapy: A Life Span Approach. Philadelphia: Lippincott, Williams & Wilkins.
Prince JB, Wilens TE, Biederman J et al. (1996), Clonidine for sleep disturbances associated with attention-deficit hyperactivity disorder: a systematic chart review of 62 cases. J Am Acad Child Adolesc Psychiatry 35(5):599-605.
Research Unit on Pediatric Psychopharmacology (RUPP) Anxiety Study Group (2001), Fluvoxamine for the treatment of anxiety disorders in children and adolescents. N Engl J Med 344(17):1279-1285 [see comments].
Rush CR, Baker RW, Wright K (1999), Acute behavioral effects and abuse potential of trazodone, zolpidem and triazolam in humans. Psychopharmacology (Berl) 144(3):220-233.
Saletu-Zyhlarz GM, Abu-Bakr MH, Anderer P et al. (2001), Insomnia related to dysthymia: polysomnographic and psychometric comparison with normal controls and acute therapeutic trials with trazodone. Neuropsychobiology 44(3):139-149.
Saletu-Zyhlarz GM, Anderer P, Arnold O, Saletu B (2003), Confirmation of the neurophysiologically predicted therapeutic effects of trazodone on its target symptoms depression, anxiety and insomnia by postmarketing clinical studies with a controlled release formulation in depressed outpatients. Neuropsychobiology 48(4):194-208.
Scheffer RE, Kowatch RA, Carmody T, Rush AJ (2005), Randomized, placebo-controlled trial of mixed amphetamine salts for symptoms of comorbid ADHD in pediatric bipolar disorder after mood stabilization with divalproex sodium. Am J Psychiatry 162(1):58-64.
Simeon JG, Ferguson HB, Knott V et al. (1992), Clinical, cognitive, and neuropsychological effects of alprazolam in children and adolescents with overanxious and avoidant disorders. J Am Acad Child Adolesc Psychiatry 31(1):29-33.
Smits MG, van Stel HF, van der Heijden K et al. (2003), Melatonin improves health status and sleep in children with idiopathic chronic sleep-onset insomnia: a randomized placebo controlled trial. J Am Acad Child Adolesc Psychiatry 42(11): 1286-1293.
Soutullo CA, DelBello MP, Ochsner JE et al. (2002), Severity of bipolarity in hospitalized manic adolescents with history of stimulant or antidepressant treatment. J Affect Disord 70(3):323-327.
Wilens TE, Biederman J, Kwon A et al. (2003), A systematic chart review of the nature of psychiatric adverse events in children and adolescents treated with selective serotonin reuptake inhibitors. J Child Adolesc Psychopharmacol 13(2):143-152.