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Combination pharmacotherapy in children and adolescents with bipolar disorder
Combination Pharmacotherapy in Children and Adolescents with Bipolar Disorder Robert A. Kowatch, Gopalan Sethuraman, Judith H. Hume, Michelle Kromelis, and Warren A. Weinberg Background: The purpose of this study was to develop prospective data on the effectiveness of combination pharmacotherapy of children and adolescents with bipolar disorder during a 6-month period of prospective, seminaturalistic treatment. Methods: Thirty-five subjects, with a mean age of 11 years, were treated in the extension phase of this study after having received 6 – 8 weeks of acute treatment with a single mood stabilizer. The extension phase of this study lasted for another 16 weeks, for a total of 24 weeks of prospective treatment. During this study phase, subjects were openly treated, and they could have their acutephase mood stabilizer switched or augmented with another mood stabilizer, a stimulant, an antidepressant agent, or antipsychotic agent, if they were assessed to be a nonresponder to monotherapy with their initial mood stabilizer. Results: During the extension phase of treatment, 20 of 35 subjects (58%) required treatment with one or two mood stabilizers and either a stimulant, an atypical antipsychotic agent, or an antidepressant agent. The response rate to combination therapy was very good, with 80% of subjects treated responding to combination therapy with two mood stabilizers after not responding to monotherapy with a mood stabilizer. Conclusions: This study suggests that children and adolescents with bipolar disorder are similar to adults with bipolar disorder, who also frequently require combination therapy. Biol Psychiatry 2003;53:978 –984 © 2003 Society of Biological Psychiatry Key Words: Bipolar disorder, children, adolescents, lithium, carbamazepine, divalproex
From the Department of Psychiatry (RAK, GS), Cincinnati Children’s Hospital Medical Center and the University of Cincinnati Medical Center, Cincinnati, Ohio; and the University of Texas Southwestern Medical Center at Dallas (JHH, MK, WAW), Dallas, Texas. Address reprint requests to Robert A. Kowatch, M.D., University of Cincinnati Medical Center, Department of Psychiatry, 231 Albert Sabin Way, 7261 Medical Sciences Building, P.O. Box 670559, Cincinnati OH 45267-0559. Received October 7, 2002; revised December 31, 2002; accepted January 9, 2003.
© 2003 Society of Biological Psychiatry
Introduction
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hildren and adolescents with bipolar disorders are similar to bipolar adults in their resistance to monotherapy with mood stabilizers. This may be because pediatric bipolar disorders are often complicated in their initial presentation and clinical course, which leads to their frequent misdiagnosis or under-recognition. Among adults with acute mania, one of the largest and best-controlled mood stabilizer studies found response rates for the treatment of acute mania of 49% for lithium and 48% for sodium divalproex (Bowden et al 1994). In the only well-controlled, prospective study of lithium carbonate in adolescents with bipolar disorder and comorbid substance abuse, Geller and colleagues reported a response to lithium at the end of 6 weeks of acute treatment of 46.2% (Geller et al 1998a). Thus, from the limited data that exist regarding the responsiveness of adolescents with mania to mood stabilizers, it appears that adolescents are as responsive to treatment with lithium as adults with mania. This means, however, that approximately 50% of adult and adolescents with mania do not respond to monotherapy with a single mood stabilizer; and to date there have been no controlled trials of any other mood stabilizers in children and adolescents with bipolar disorders. Another cause of pediatric bipolar patients’ treatment resistance may be that they often present with a mixed or “dysphoric” picture, characterized by frequent short periods of intense mood lability and irritability rather than classic euphoric mania (Faedda et al 1995). Geller and colleagues reported that in 26 bipolar children and adolescents, “complex” cycling patterns, characterized by brief manic periods lasting 4 or more hours, occurred in 81% of their patients (Geller et al 1995). There is a growing consensus among experts in adult bipolar disorders that monotherapy with either lithium or sodium divalproex may not be sufficient either for maintenance treatment of patients with bipolar disorders, or for the treatment of a manic episode in patients with mixed and/or rapid-cycling mania (Frye et al 2000; Post 1993; Prien and Rush 1996; Solomon et al 1996). Biederman and colleagues recently performed a chart review of 59 subjects in a university 0006-3223/03/$30.00 doi:10.1016/S0002-3223(03)00067-2
Polypharmacy in Pediatric Bipolar Disorder
psychopharmacology clinic meeting DSM-III-R criteria for mania and reported that 42% of these patients were treated with a mood stabilizer and a selective serotonin reuptake inhibitor (SSRI), 42% with a mood stabilizer and a stimulant, and 50% with a mood stabilizer and a tricyclic antidepressant (Biederman et al 1998). They also reported that treatment with mood stabilizers predicted improvement in manic symptoms independent of other psychotropic medications. Children and adolescents with pediatric bipolar disorders often have comorbid disorders that also complicate their diagnosis and treatment response. These comorbid disorders include attention-deficit/hyperactivity disorder (ADHD), anxiety disorders, oppositional defiant disorder, and conduct disorder (Kovacs and Pollock 1995; West et al 1995; Wozniak et al 1995). Attention-deficit/hyperactivity disorder is the most common comorbid disorder among these patients, with some groups finding comorbid rates as high as 98% (Wozniak et al 1995; Geller et al 1998b). Pediatric bipolar disorder with comorbid ADHD can be difficult to treat because of the fear of exacerbating the patient’s mood disorder while treating ADHD with stimulants. Yet in 1992 Carlson and colleagues reported a “synergistic rather than an antagonistic effect” of lithium and methylphenidate in seven hospitalized children with DSM-III-R bipolar disorder not otherwise specified and disruptive behavior disorders (Carlson et al 1992). Biederman and colleagues reported on 38 pediatric patients who were diagnosed with DSM-III-R mania and ADHD and treated first with mood stabilizers and then stimulants. They found that those patients who first had their mania treated with mood stabilizers responded very well to the addition of a stimulant medication (Biederman et al 1999). There have been two recent studies of the efficacy of mood stabilizers combined with antipsychotics in adolescent inpatients with bipolar disorder. In the first study, Kafantaris and coworkers evaluated acutely manic adolescents with psychotic features after treatment with lithium and an adjunctive antipsychotic medication. If their psychosis resolved, the antipsychotic medication dose was gradually tapered and discontinued after 4 weeks of therapeutic lithium levels (Kafantaris et al 2001). The patients were then given a trial of maintenance lithium monotherapy for up to 4 weeks. Significant improvement was seen in 64% of the sample with psychotic features after 4 weeks of combination treatment; however, 43% did not maintain their response after discontinuation of the antipsychotic medication, suggesting that more than 4 weeks of antipsychotic treatment is required for some adolescents with psychotic mania. In the second study, DelBello and colleagues published the results of a doubleblind, placebo-controlled study that examined the efficacy, safety, and tolerability of quetiapine as an adjunct to
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divalproex for acute mania in adolescents with bipolar disorder (DelBello et al 2002). In this study, 30 manic or mixed bipolar I adolescent inpatients, ages 12–18 years, received an initial divalproex dose of 20 mg/kg and were randomized to 6 weeks of quetiapine, which was titrated to 450 mg/day (n ⫽ 15), or placebo (n ⫽ 15). The divalproex ⫹ quetiapine group demonstrated a statistically significantly greater reduction in Young Mania Rating Scale (Y-MRS) scores from baseline to end point than the divalproex ⫹ placebo group. The findings of this study indicated that quetiapine in combination with divalproex was more effective for the treatment of adolescent bipolar mania than divalproex alone. In 1999, we completed an acute-phase study of the pharmacologic treatment of children and adolescents with bipolar disorders (Kowatch et al 2000). In this study, with a treatment duration of 6 – 8 weeks, we aimed at developing effect sizes (Cohen 1988) for lithium, divalproex, and carbamazepine, in the acute phase treatment of bipolar I or II disorder (manic or hypomanic) children and adolescents. The effect size (Cohen’s d) for each group using the change from baseline to end point in the weekly Y-MRS and the modified intent-to-treat sample was divalproex 1.63; lithium 1.06; and carbamazepine 1.00. During the acute phase of treatment, there was no significant difference between these three groups using a Clinical Global Impression (CGI) Improvement score of 1 or 2 criteria or using a 50% improvement in Y-MRS score criteria. The divalproex sodium group had response rates of 40% and 53% using the CGI criteria and Y-MRS criteria, and the lithium group had response rates of 46% and 38%. The carbamazepine group had the fewest responders (31% using the CGI criteria, 38% using the Y-MRS criteria). The extension phase of this study lasted for another 16 weeks, for a total of 24 weeks of prospective treatment. During this study phase, subjects were openly treated, and they could have their acute-phase mood stabilizer switched or augmented with another mood stabilizer, a stimulant, an antidepressant agent, or antipsychotic agent, if they were assessed to be a nonresponder to monotherapy with their mood stabilizer. The purpose of this study was to develop prospective data on the effectiveness of combination therapy in bipolar children and adolescents during a 6-month period of treatment.
Methods and Materials Subjects included in this study were recruited from an outpatient child psychiatry service, and this study was approved by the local university institutional review board. Informed consent was obtained from the subject and their guardian after the nature of the experimental treatment was explained. Subjects had to meet DSM-IV (American Psychiatric Association 2000) inclusion criteria for bipolar I or II disorder, during a mixed, manic, or
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hypomanic episode and be 7–18 years old. They had to score ⬎14 on the Y-MRS (Young et al 1978) at entry into the acute phase of treatment, to have no current general medical illnesses that required medication, and have normal intelligence as estimated by their academic performance and placement. Excluded were those with current or lifetime diagnoses of schizophrenia, obsessive-compulsive disorder, or autistic disorder; those with substance abuse or dependence; and a history of organic brain disease. Patients were initially seen for a 2-week evaluation period during the acute phase and underwent structured interviews and laboratory testing. The Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS; Kaufman et al 1997) was administered to the parent (usually the mother) and child separately by a research assistant who had established reliability and then verified by the principal investigator (RAK), who is board certified in child and adolescent psychiatry. Subject’s level of functioning was rated using the Children’s Clinical Global Assessment Scale (CGAS; Shaffer et al 1983). The primary efficacy measure was the change in Y-MRS from entry to exit, with response defined as a ⬎50% improvement. Subjects were seen every 2–3 weeks with their parent(s), and at each visit they were rated on the Y-MRS, the CGI-Bipolar Scale, a side effects scale, and the K-SADS Mania and Depression items. Response of ADHD symptoms was defined as “much” or “very much improved” (a score of 1 or 2) on the CGAS (National Institute of Mental Health 1985). At the end of the acute phase of treatment with one mood stabilizer, subjects could have their initial mood stabilizer changed or augmented by the study physician, who had also treated these subjects in the acute phase of this study (RAK). These treatment options were as follows: 1. If subjects were doing well clinically and categorized as a responder on the Y-MRS, then they could continue in open treatment on whatever single mood stabilizer they were on, and they were followed for another 16 –18 weeks. 2. If the subject was not doing well clinically and categorized as a nonresponder, then the following options were available to the treating clinician: A. If bipolar symptoms were judged to be predominant, then another mood stabilizer could be added to the subject’s acute phase mood stabilizer. B. If the patient was intolerant of their first mood stabilizer, then he or she could be switched to another mood stabilizer. C. If ADHD symptoms were judged to be predominant and the patient’s mood was stable, then the subject could be started on a low dose (5–10 mg) of methylphenidate b.i.d., in addition to the mood stabilizer(s) with which he or she was already treated. D. If depressive symptoms were present, then the subject could be treated with either bupropion or an SSRI, in addition to the mood stabilizer with which he or she was already treated. E. If psychotic symptoms were present, then the subject could be treated with an atypical antipsychotic agent in
Figure 1. Subject flow during study.
addition to the mood stabilizer with which he or she was already treated. Descriptive statistics are provided on this sample of 35 subjects. We elected to describe these results in two ways: by the response status of subjects at entry into the extension phase study versus their response status at the end of the extension phase; and by the number of medications they were treated with during the extension phase. Fifteen subjects were treated with only a single mood stabilizer and no other psychotropics, whereas 20 subjects required treatment with two mood stabilizers and in some cases an antidepressant agent, an antipsychotic agent, or a psychostimulant. This latter group was referred to as the “combination therapy group.” Grouping subjects by their response status resulted in three groups of subjects at the end of the extension phase: 1. Acute-phase responders who were responders when they exited the extension phase; 2. Acute-phase nonresponders who were responders when they exited the extension phase; and 3. Acute-phase nonresponders who were nonresponders when they exited the extension phase. The flow of these subjects during the extension phase of treatment is illustrated in Figure 1.
Results Seven subjects dropped out of treatment before entering the extension phase of treatment. Of these seven, four were male and three were female, and their mean age was 13.4 years. The mean Y-MRS score for these subjects at the time of exit was 14.6. Of these seven subjects, at the time they withdrew from the study, two were responders and five were nonresponders. One 9-year-old boy was withdrawn in the second week of acute treatment after he developed a rash while treated with carbamazepine; one 16-year-old boy was withdrawn at week 6 after testing
Polypharmacy in Pediatric Bipolar Disorder
Table 1. Demographic, Severity, and Clinical Characteristics of Subjects at Entry to the Extension Phase Characteristic Subjects (n) Age (years) Gender (male) Hollingshead SES Current Grade in School Mania/Bipolar I CGAS YMRS Psychosis Family Global Assessment Scale Score Age Onset Bipolar Symptoms (years) Comorbid ADHD ADHD Age Onset (years) Duration-Bipolar Symptoms (years) Prior Psychotherapy (%) Prior Psychotropic Medications (%) Age Started Stimulant Treatment (years)
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35 11 ⫾ 2.8 22 (63) 3.0 ⫾ .62 5.5 ⫾ 3.5 17/35 (48) 48 ⫾ 8.1 28 ⫾ 5 4 (11) 69 ⫾ 11.8 7.0 ⫾ 3.1 28/35 (80) 5.4 ⫾ 2.8 4.4 ⫾ 2.5 77 80 6.9 ⫾ 2.9
Values are mean ⫾ SD or n (%) unless otherwise noted. SES, socioeconomic score; CGAS, Children’s Clinical Global Assessment; YMRS, Young Mania Rating Scale; ADHD, attention-deficit/hyperactivity disorder.
positive for opiates; the other five subjects, all adolescents, were withdrawn due to medication noncompliance. Thirty-five subjects elected to continue in the extension phase of the study after 6 – 8 weeks of acute treatment with a single mood stabilizer. Seventeen of these subjects (48%) were manic, and 18 were hypomanic. Table 1 presents the demographic and severity data of the subjects in the extension phase of this study. There were significantly more male subjects in the prepubertal group (73%) and significantly more male subjects diagnosed with bipolar II/hypomania (77%). At entry into the extension phase, the subjects’ mean Y-MRS was 28 ⫾ 5 and CGAS score was 48 ⫾ 8. The bipolar I subjects had a lower CGAS score (45) than the bipolar II subjects (52). There were high rates of other psychiatric disorders, particularly ADHD (80%), oppositional defiant disorder (38%), and anxiety disorders (17%). At the start of the extension phase of treatment there were 18 acute-phase responders and 17 acute-phase nonresponders. The mean age of the responders was 11.6 years and their mean Y-MRS score was 8.4. The mean age of the nonresponders was 10.4 years and their mean
Table 3. Nonresponders at Entry/Responders at Exit Treatment during Extension Phase
Mood Stabilizer Patient Received During the Acute Treatment Phase (n)
Lithium ⫹ Divalproex
Divalproex
4 0 3
1 2 2 ⫹ AP
Lithium (5) Carbamazepine (2) Divalproex (5) Values are n. AP, antipsychotic agent.
Y-MRS score was 26.3. At end of the extension phase of the study, there were 30 responders (19 male, 11 female) and five nonresponders (three male, two female). The mean age of the 30 responders was 11.3 years, and the mean age of the five nonresponders was 9.8 years.
Group ⫻ Response Category There were 18 subjects in the responders at entry/responders at exit group. Of the six subjects treated initially with lithium, three continued to respond to lithium, whereas three subjects required augmentation with a second mood stabilizer— one with carbamazepine and two with divalproex sodium. Of the four subjects treated with carbamazepine, all four continued to respond to carbamazepine. Of the eight subjects treated with divalproex sodium, six continued to respond to divalproex and two required augmentation with lithium. The course of these subjects is illustrated in Table 2. There were 12 subjects who entered the extension phase as nonresponders and exited as responders: five treated in the acute phase with lithium; two with carbamazepine; and five with divalproex (see Table 3). Of the five subjects treated initially with lithium, four subjects responded to augmentation with divalproex, and one subject responded when switched to divalproex. Of the two nonresponding subjects treated with carbamazepine, one subject was treated with carbamazepine and divalproex, but serum levels of both of these mood stabilizers became erratic so the carbamazepine was discontinued and the subject subsequently responded to divalproex; another subject treated with carbamazepine was unable to tolerate continued
Table 2. Responders at Entry/Responders at Exit Mood Stabilizer Patient Received during the Acute Treatment Phase (n) Lithium (6) Carbamazepine (4) Divalproex (8) Values are n.
Treatment during Extension Phase Lithium
Carbamazepine
Divalproex
Carbamazepine ⫹ Divalproex
Lithium ⫹ Divalproex
3 0 0
0 4 0
0 0 6
1 0 0
2 0 2
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Table 4. Nonresponders at Entry/Nonresponders at Exit Mood Stabilizer Patient Received during the Acute Treatment Phase (n) Lithium (1) Carbamazepine (3) Divalproex (1)
Treatment during Extension Phase Lithium ⫹ Divalproex
Divalproex
1 (⫹ AP) 2 (1 with AP) 1
0 1 0
Values are n. AP, antipsychotic agent.
treatment with carbamazepine because of side effects and responded when switched to divalproex. Of the five nonresponding subjects treated with divalproex, three responded to augmentation with lithium, and two responded to augmentation with risperidone (both of these subjects had developed psychotic symptoms during the extension phase). There were five subjects who were nonresponders at entry and nonresponders at exit (Table 4). One subject treated initially with lithium failed to respond to augmentation with divalproex and risperidone. Three subjects treated with carbamazepine failed to respond to augmentation or mood stabilizer switch: one subject who was switched to divalproex; one subject who was switched to divalproex plus lithium and risperidone; and one subject who was switched to divalproex plus lithium. One subject treated with divalproex failed to respond to augmentation with lithium. These subjects exited the extension phase while in a mixed state and were not psychotic or depressed when they exited the protocol.
Groups ⫻ Type of Treatment Over all, 15 of 35 (42%) subjects were treated with a single mood stabilizer and no other psychotropic agents. The response rate in this group was 94% (13 of 15 subjects). At the start of the extension phase, the mean age of these subjects (eight male, seven female) was 11.4 ⫾ 3 years, mean CGAS score was 49.6 ⫾ 7, mean Y-MRS score was 12 ⫾ 10, and mean socioeconomic score was 3.1 ⫾ .7. Seven of these subjects were treated during the acute phase with carbamazepine, five with divalproex, and three with lithium. Four of the seven carbamazepinetreated subjects maintained their response to carbamazepine, whereas one subject responded when switched to divalproex, one subject did not respond when switched to divalproex, and one subject remained on carbamazepine and was a nonresponder at the end of the extension treatment period. Of the three lithium-treated subjects who were responders during the acute phase, two maintained their response, whereas one nonresponding subject was switched to divalproex because of adverse effects and subsequently responded to divalproex. Four subjects
treated with divalproex maintained their positive response through the extension phase of treatment, and one subject who was a nonresponder during the acute phase responded to divalproex during the extension phase. Of 35 subjects, 20 (58%) required combination treatment, and the overall response rate to combination therapy was 80% (16 of 20 subjects). The combination treatment group included 12 of 35 (34%) with two mood stabilizers and a stimulant; four of 35 (11%) with two mood stabilizers and an antipsychotic agent; and two of 35 (6%) with two mood stabilizers and an antidepressant agent. Twelve of 13 patients who had a stimulant added to their mood stabilizer(s) had a positive response on the CGI Improvement Scale for ADHD symptoms—an overall response rate of 92%. There were no serious adverse effects during the course of treatment with any of these subjects. In all cases, augmentation and combination treatment was well tolerated.
Discussion During the extension phase of treatment, 20 of 35 subjects (58%) required treatment with one or two mood stabilizers and either a stimulant, an atypical antipsychotic agent, or an antidepressant agent. The response rate to combination therapy was very good, with 16 of 20 subjects treated (80%) responding to combination therapy with two mood stabilizers after not responding to a single mood stabilizer during the acute phase of treatment. This suggests that children and adolescents with bipolar disorders are similar to adult bipolar patients, who also frequently require treatment with multiple medications (Frye et al 2000). The group that responded to treatment with a single mood stabilizer did not differ in any obvious way from the combination treatment in terms of past exposure to psychotropic medication, severity, age, or gender. Three of these 15 subjects were switched to another mood stabilizer before they became responders. This was usually done because they could not tolerate the initial mood stabilizer because of side effects. Only two subjects required the addition of an antidepressant agent for an episode of major depression. In both of these cases, an SSRI was added to the single mood stabilizer the subject was taking (lithium in one subject, divalproex in the other), with a good antidepressant response. This low rate of major depression may have been due to the fact that all of these subjects were treated aggressively with one or two mood stabilizers. Among adults with bipolar disorders, the use of mood stabilizers is thought to markedly lower the rate of major depressive episodes. The low rate of depressive episodes may also have been due to the relatively young age of our subjects (mean age of 11 ⫾ 2.9 years), as our clinical experience
Polypharmacy in Pediatric Bipolar Disorder
has been that major depressive episodes are more common once these bipolar patients reach adolescence. A significant proportion of these pediatric bipolar subjects required treatment of comorbid ADHD before they became improved in overall functioning—mood and attention. The typical clinical presentation was that of a prepubertal child who was diagnosed with ADHD at early age and subsequently treated with stimulants at approximately 4 –5 years of age. Then, usually at the age of 7– 8 years, the child’s bipolar symptoms would become very severe. In the majority of such cases, even after stimulant medications were discontinued, the child would continue to manifest severe mood lability and other bipolar symptoms. Once started on a mood stabilizer, their moods would improve, but they would continue to manifest ADHD symptoms. Our experience in this study was that the addition of a low-dose stimulant to this subject’s mood stabilizers would in many cases markedly improve the child’s ADHD symptoms without exacerbating the mood disorder. This finding runs against the prevailing clinical wisdom, which holds that stimulants may exacerbate manic symptoms in bipolar patients (DelBello et al 2001; Goodwin and Jamison 1990). Yet there are some reports that show this is not always the case in bipolar children and adolescents. Max et al (1995) reported an excellent response to dextroamphetamine in a 14-year-old male with an organic bipolar disorder. Our preliminary data, and those of others, indicate that children and adolescents with bipolar disorders frequently have comorbid ADHD that requires treatment in addition to their bipolar disorder. Our data and the data of others suggests that if a pediatric bipolar patient with comorbid ADHD is first stabilized on one or more mood stabilizers, then the addition of a stimulant is often very helpful in treating their comorbid ADHD (Biederman et al 1999). The critical issue appears to be the sequence of treatment, with the patient’s bipolar disorder treated before stimulant medication is added or reintroduced. This study is limited by its small sample size, the variable length of treatment during the acute phase, lack of a double blind, and lack of strict criteria for the addition of psychotropic agents. All of these subjects were outpatients, which limits the generalizability of these results to inpatient samples, for whom the severity and chronicity of the bipolar disorders is often greater. The long-term pharmacologic management of bipolar children and adolescents is often complicated by comorbid conditions, including ADHD, depression, and psychosis. The successful management of these patients frequently requires the use of combined mood stabilizers and other psychotropic agents. Further controlled studies of combination therapy are desperately needed in children and adolescents with bipolar disorders.
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Support is gratefully acknowledged from the National Alliance for the Mentally Ill/Stanley Foundation Research Awards Program and the National Institute of Mental Health, grant K07-MH01057 (RAK). WAW was funded by The Caleb C. and Julia W. Dula Education and Charitable Foundations, Mr. and Mrs. Woody Hunt, Mr. and Mrs. Morton Myerson, and the Azoulay Family. Aspects of this work were presented at the conference, “Pediatric Bipolar Disorder,” held March 9, 2002 in Boston, Massachusetts. The conference was sponsored by the Massachusetts General Hospital through and unrestricted educational grant provided by Janssen Pharmaceutica.
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From the Department of Psychiatry (RAK, GS), Cincinnati Children’s Hospital Medical Center and the University of Cincinnati Medical Center, Cincinnati, Ohio; and the University of Texas Southwestern Medical Center at Dallas (JHH, MK, WAW), Dallas, Texas. Address reprint requests to Robert A. Kowatch, M.D., University of Cincinnati Medical Center, Department of Psychiatry, 231 Albert Sabin Way, 7261 Medical Sciences Building, P.O. Box 670559, Cincinnati OH 45267-0559. Received October 7, 2002; revised December 31, 2002; accepted January 9, 2003.
© 2003 Society of Biological Psychiatry
Introduction
C
hildren and adolescents with bipolar disorders are similar to bipolar adults in their resistance to monotherapy with mood stabilizers. This may be because pediatric bipolar disorders are often complicated in their initial presentation and clinical course, which leads to their frequent misdiagnosis or under-recognition. Among adults with acute mania, one of the largest and best-controlled mood stabilizer studies found response rates for the treatment of acute mania of 49% for lithium and 48% for sodium divalproex (Bowden et al 1994). In the only well-controlled, prospective study of lithium carbonate in adolescents with bipolar disorder and comorbid substance abuse, Geller and colleagues reported a response to lithium at the end of 6 weeks of acute treatment of 46.2% (Geller et al 1998a). Thus, from the limited data that exist regarding the responsiveness of adolescents with mania to mood stabilizers, it appears that adolescents are as responsive to treatment with lithium as adults with mania. This means, however, that approximately 50% of adult and adolescents with mania do not respond to monotherapy with a single mood stabilizer; and to date there have been no controlled trials of any other mood stabilizers in children and adolescents with bipolar disorders. Another cause of pediatric bipolar patients’ treatment resistance may be that they often present with a mixed or “dysphoric” picture, characterized by frequent short periods of intense mood lability and irritability rather than classic euphoric mania (Faedda et al 1995). Geller and colleagues reported that in 26 bipolar children and adolescents, “complex” cycling patterns, characterized by brief manic periods lasting 4 or more hours, occurred in 81% of their patients (Geller et al 1995). There is a growing consensus among experts in adult bipolar disorders that monotherapy with either lithium or sodium divalproex may not be sufficient either for maintenance treatment of patients with bipolar disorders, or for the treatment of a manic episode in patients with mixed and/or rapid-cycling mania (Frye et al 2000; Post 1993; Prien and Rush 1996; Solomon et al 1996). Biederman and colleagues recently performed a chart review of 59 subjects in a university 0006-3223/03/$30.00 doi:10.1016/S0002-3223(03)00067-2
Polypharmacy in Pediatric Bipolar Disorder
psychopharmacology clinic meeting DSM-III-R criteria for mania and reported that 42% of these patients were treated with a mood stabilizer and a selective serotonin reuptake inhibitor (SSRI), 42% with a mood stabilizer and a stimulant, and 50% with a mood stabilizer and a tricyclic antidepressant (Biederman et al 1998). They also reported that treatment with mood stabilizers predicted improvement in manic symptoms independent of other psychotropic medications. Children and adolescents with pediatric bipolar disorders often have comorbid disorders that also complicate their diagnosis and treatment response. These comorbid disorders include attention-deficit/hyperactivity disorder (ADHD), anxiety disorders, oppositional defiant disorder, and conduct disorder (Kovacs and Pollock 1995; West et al 1995; Wozniak et al 1995). Attention-deficit/hyperactivity disorder is the most common comorbid disorder among these patients, with some groups finding comorbid rates as high as 98% (Wozniak et al 1995; Geller et al 1998b). Pediatric bipolar disorder with comorbid ADHD can be difficult to treat because of the fear of exacerbating the patient’s mood disorder while treating ADHD with stimulants. Yet in 1992 Carlson and colleagues reported a “synergistic rather than an antagonistic effect” of lithium and methylphenidate in seven hospitalized children with DSM-III-R bipolar disorder not otherwise specified and disruptive behavior disorders (Carlson et al 1992). Biederman and colleagues reported on 38 pediatric patients who were diagnosed with DSM-III-R mania and ADHD and treated first with mood stabilizers and then stimulants. They found that those patients who first had their mania treated with mood stabilizers responded very well to the addition of a stimulant medication (Biederman et al 1999). There have been two recent studies of the efficacy of mood stabilizers combined with antipsychotics in adolescent inpatients with bipolar disorder. In the first study, Kafantaris and coworkers evaluated acutely manic adolescents with psychotic features after treatment with lithium and an adjunctive antipsychotic medication. If their psychosis resolved, the antipsychotic medication dose was gradually tapered and discontinued after 4 weeks of therapeutic lithium levels (Kafantaris et al 2001). The patients were then given a trial of maintenance lithium monotherapy for up to 4 weeks. Significant improvement was seen in 64% of the sample with psychotic features after 4 weeks of combination treatment; however, 43% did not maintain their response after discontinuation of the antipsychotic medication, suggesting that more than 4 weeks of antipsychotic treatment is required for some adolescents with psychotic mania. In the second study, DelBello and colleagues published the results of a doubleblind, placebo-controlled study that examined the efficacy, safety, and tolerability of quetiapine as an adjunct to
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divalproex for acute mania in adolescents with bipolar disorder (DelBello et al 2002). In this study, 30 manic or mixed bipolar I adolescent inpatients, ages 12–18 years, received an initial divalproex dose of 20 mg/kg and were randomized to 6 weeks of quetiapine, which was titrated to 450 mg/day (n ⫽ 15), or placebo (n ⫽ 15). The divalproex ⫹ quetiapine group demonstrated a statistically significantly greater reduction in Young Mania Rating Scale (Y-MRS) scores from baseline to end point than the divalproex ⫹ placebo group. The findings of this study indicated that quetiapine in combination with divalproex was more effective for the treatment of adolescent bipolar mania than divalproex alone. In 1999, we completed an acute-phase study of the pharmacologic treatment of children and adolescents with bipolar disorders (Kowatch et al 2000). In this study, with a treatment duration of 6 – 8 weeks, we aimed at developing effect sizes (Cohen 1988) for lithium, divalproex, and carbamazepine, in the acute phase treatment of bipolar I or II disorder (manic or hypomanic) children and adolescents. The effect size (Cohen’s d) for each group using the change from baseline to end point in the weekly Y-MRS and the modified intent-to-treat sample was divalproex 1.63; lithium 1.06; and carbamazepine 1.00. During the acute phase of treatment, there was no significant difference between these three groups using a Clinical Global Impression (CGI) Improvement score of 1 or 2 criteria or using a 50% improvement in Y-MRS score criteria. The divalproex sodium group had response rates of 40% and 53% using the CGI criteria and Y-MRS criteria, and the lithium group had response rates of 46% and 38%. The carbamazepine group had the fewest responders (31% using the CGI criteria, 38% using the Y-MRS criteria). The extension phase of this study lasted for another 16 weeks, for a total of 24 weeks of prospective treatment. During this study phase, subjects were openly treated, and they could have their acute-phase mood stabilizer switched or augmented with another mood stabilizer, a stimulant, an antidepressant agent, or antipsychotic agent, if they were assessed to be a nonresponder to monotherapy with their mood stabilizer. The purpose of this study was to develop prospective data on the effectiveness of combination therapy in bipolar children and adolescents during a 6-month period of treatment.
Methods and Materials Subjects included in this study were recruited from an outpatient child psychiatry service, and this study was approved by the local university institutional review board. Informed consent was obtained from the subject and their guardian after the nature of the experimental treatment was explained. Subjects had to meet DSM-IV (American Psychiatric Association 2000) inclusion criteria for bipolar I or II disorder, during a mixed, manic, or
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hypomanic episode and be 7–18 years old. They had to score ⬎14 on the Y-MRS (Young et al 1978) at entry into the acute phase of treatment, to have no current general medical illnesses that required medication, and have normal intelligence as estimated by their academic performance and placement. Excluded were those with current or lifetime diagnoses of schizophrenia, obsessive-compulsive disorder, or autistic disorder; those with substance abuse or dependence; and a history of organic brain disease. Patients were initially seen for a 2-week evaluation period during the acute phase and underwent structured interviews and laboratory testing. The Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS; Kaufman et al 1997) was administered to the parent (usually the mother) and child separately by a research assistant who had established reliability and then verified by the principal investigator (RAK), who is board certified in child and adolescent psychiatry. Subject’s level of functioning was rated using the Children’s Clinical Global Assessment Scale (CGAS; Shaffer et al 1983). The primary efficacy measure was the change in Y-MRS from entry to exit, with response defined as a ⬎50% improvement. Subjects were seen every 2–3 weeks with their parent(s), and at each visit they were rated on the Y-MRS, the CGI-Bipolar Scale, a side effects scale, and the K-SADS Mania and Depression items. Response of ADHD symptoms was defined as “much” or “very much improved” (a score of 1 or 2) on the CGAS (National Institute of Mental Health 1985). At the end of the acute phase of treatment with one mood stabilizer, subjects could have their initial mood stabilizer changed or augmented by the study physician, who had also treated these subjects in the acute phase of this study (RAK). These treatment options were as follows: 1. If subjects were doing well clinically and categorized as a responder on the Y-MRS, then they could continue in open treatment on whatever single mood stabilizer they were on, and they were followed for another 16 –18 weeks. 2. If the subject was not doing well clinically and categorized as a nonresponder, then the following options were available to the treating clinician: A. If bipolar symptoms were judged to be predominant, then another mood stabilizer could be added to the subject’s acute phase mood stabilizer. B. If the patient was intolerant of their first mood stabilizer, then he or she could be switched to another mood stabilizer. C. If ADHD symptoms were judged to be predominant and the patient’s mood was stable, then the subject could be started on a low dose (5–10 mg) of methylphenidate b.i.d., in addition to the mood stabilizer(s) with which he or she was already treated. D. If depressive symptoms were present, then the subject could be treated with either bupropion or an SSRI, in addition to the mood stabilizer with which he or she was already treated. E. If psychotic symptoms were present, then the subject could be treated with an atypical antipsychotic agent in
Figure 1. Subject flow during study.
addition to the mood stabilizer with which he or she was already treated. Descriptive statistics are provided on this sample of 35 subjects. We elected to describe these results in two ways: by the response status of subjects at entry into the extension phase study versus their response status at the end of the extension phase; and by the number of medications they were treated with during the extension phase. Fifteen subjects were treated with only a single mood stabilizer and no other psychotropics, whereas 20 subjects required treatment with two mood stabilizers and in some cases an antidepressant agent, an antipsychotic agent, or a psychostimulant. This latter group was referred to as the “combination therapy group.” Grouping subjects by their response status resulted in three groups of subjects at the end of the extension phase: 1. Acute-phase responders who were responders when they exited the extension phase; 2. Acute-phase nonresponders who were responders when they exited the extension phase; and 3. Acute-phase nonresponders who were nonresponders when they exited the extension phase. The flow of these subjects during the extension phase of treatment is illustrated in Figure 1.
Results Seven subjects dropped out of treatment before entering the extension phase of treatment. Of these seven, four were male and three were female, and their mean age was 13.4 years. The mean Y-MRS score for these subjects at the time of exit was 14.6. Of these seven subjects, at the time they withdrew from the study, two were responders and five were nonresponders. One 9-year-old boy was withdrawn in the second week of acute treatment after he developed a rash while treated with carbamazepine; one 16-year-old boy was withdrawn at week 6 after testing
Polypharmacy in Pediatric Bipolar Disorder
Table 1. Demographic, Severity, and Clinical Characteristics of Subjects at Entry to the Extension Phase Characteristic Subjects (n) Age (years) Gender (male) Hollingshead SES Current Grade in School Mania/Bipolar I CGAS YMRS Psychosis Family Global Assessment Scale Score Age Onset Bipolar Symptoms (years) Comorbid ADHD ADHD Age Onset (years) Duration-Bipolar Symptoms (years) Prior Psychotherapy (%) Prior Psychotropic Medications (%) Age Started Stimulant Treatment (years)
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35 11 ⫾ 2.8 22 (63) 3.0 ⫾ .62 5.5 ⫾ 3.5 17/35 (48) 48 ⫾ 8.1 28 ⫾ 5 4 (11) 69 ⫾ 11.8 7.0 ⫾ 3.1 28/35 (80) 5.4 ⫾ 2.8 4.4 ⫾ 2.5 77 80 6.9 ⫾ 2.9
Values are mean ⫾ SD or n (%) unless otherwise noted. SES, socioeconomic score; CGAS, Children’s Clinical Global Assessment; YMRS, Young Mania Rating Scale; ADHD, attention-deficit/hyperactivity disorder.
positive for opiates; the other five subjects, all adolescents, were withdrawn due to medication noncompliance. Thirty-five subjects elected to continue in the extension phase of the study after 6 – 8 weeks of acute treatment with a single mood stabilizer. Seventeen of these subjects (48%) were manic, and 18 were hypomanic. Table 1 presents the demographic and severity data of the subjects in the extension phase of this study. There were significantly more male subjects in the prepubertal group (73%) and significantly more male subjects diagnosed with bipolar II/hypomania (77%). At entry into the extension phase, the subjects’ mean Y-MRS was 28 ⫾ 5 and CGAS score was 48 ⫾ 8. The bipolar I subjects had a lower CGAS score (45) than the bipolar II subjects (52). There were high rates of other psychiatric disorders, particularly ADHD (80%), oppositional defiant disorder (38%), and anxiety disorders (17%). At the start of the extension phase of treatment there were 18 acute-phase responders and 17 acute-phase nonresponders. The mean age of the responders was 11.6 years and their mean Y-MRS score was 8.4. The mean age of the nonresponders was 10.4 years and their mean
Table 3. Nonresponders at Entry/Responders at Exit Treatment during Extension Phase
Mood Stabilizer Patient Received During the Acute Treatment Phase (n)
Lithium ⫹ Divalproex
Divalproex
4 0 3
1 2 2 ⫹ AP
Lithium (5) Carbamazepine (2) Divalproex (5) Values are n. AP, antipsychotic agent.
Y-MRS score was 26.3. At end of the extension phase of the study, there were 30 responders (19 male, 11 female) and five nonresponders (three male, two female). The mean age of the 30 responders was 11.3 years, and the mean age of the five nonresponders was 9.8 years.
Group ⫻ Response Category There were 18 subjects in the responders at entry/responders at exit group. Of the six subjects treated initially with lithium, three continued to respond to lithium, whereas three subjects required augmentation with a second mood stabilizer— one with carbamazepine and two with divalproex sodium. Of the four subjects treated with carbamazepine, all four continued to respond to carbamazepine. Of the eight subjects treated with divalproex sodium, six continued to respond to divalproex and two required augmentation with lithium. The course of these subjects is illustrated in Table 2. There were 12 subjects who entered the extension phase as nonresponders and exited as responders: five treated in the acute phase with lithium; two with carbamazepine; and five with divalproex (see Table 3). Of the five subjects treated initially with lithium, four subjects responded to augmentation with divalproex, and one subject responded when switched to divalproex. Of the two nonresponding subjects treated with carbamazepine, one subject was treated with carbamazepine and divalproex, but serum levels of both of these mood stabilizers became erratic so the carbamazepine was discontinued and the subject subsequently responded to divalproex; another subject treated with carbamazepine was unable to tolerate continued
Table 2. Responders at Entry/Responders at Exit Mood Stabilizer Patient Received during the Acute Treatment Phase (n) Lithium (6) Carbamazepine (4) Divalproex (8) Values are n.
Treatment during Extension Phase Lithium
Carbamazepine
Divalproex
Carbamazepine ⫹ Divalproex
Lithium ⫹ Divalproex
3 0 0
0 4 0
0 0 6
1 0 0
2 0 2
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Table 4. Nonresponders at Entry/Nonresponders at Exit Mood Stabilizer Patient Received during the Acute Treatment Phase (n) Lithium (1) Carbamazepine (3) Divalproex (1)
Treatment during Extension Phase Lithium ⫹ Divalproex
Divalproex
1 (⫹ AP) 2 (1 with AP) 1
0 1 0
Values are n. AP, antipsychotic agent.
treatment with carbamazepine because of side effects and responded when switched to divalproex. Of the five nonresponding subjects treated with divalproex, three responded to augmentation with lithium, and two responded to augmentation with risperidone (both of these subjects had developed psychotic symptoms during the extension phase). There were five subjects who were nonresponders at entry and nonresponders at exit (Table 4). One subject treated initially with lithium failed to respond to augmentation with divalproex and risperidone. Three subjects treated with carbamazepine failed to respond to augmentation or mood stabilizer switch: one subject who was switched to divalproex; one subject who was switched to divalproex plus lithium and risperidone; and one subject who was switched to divalproex plus lithium. One subject treated with divalproex failed to respond to augmentation with lithium. These subjects exited the extension phase while in a mixed state and were not psychotic or depressed when they exited the protocol.
Groups ⫻ Type of Treatment Over all, 15 of 35 (42%) subjects were treated with a single mood stabilizer and no other psychotropic agents. The response rate in this group was 94% (13 of 15 subjects). At the start of the extension phase, the mean age of these subjects (eight male, seven female) was 11.4 ⫾ 3 years, mean CGAS score was 49.6 ⫾ 7, mean Y-MRS score was 12 ⫾ 10, and mean socioeconomic score was 3.1 ⫾ .7. Seven of these subjects were treated during the acute phase with carbamazepine, five with divalproex, and three with lithium. Four of the seven carbamazepinetreated subjects maintained their response to carbamazepine, whereas one subject responded when switched to divalproex, one subject did not respond when switched to divalproex, and one subject remained on carbamazepine and was a nonresponder at the end of the extension treatment period. Of the three lithium-treated subjects who were responders during the acute phase, two maintained their response, whereas one nonresponding subject was switched to divalproex because of adverse effects and subsequently responded to divalproex. Four subjects
treated with divalproex maintained their positive response through the extension phase of treatment, and one subject who was a nonresponder during the acute phase responded to divalproex during the extension phase. Of 35 subjects, 20 (58%) required combination treatment, and the overall response rate to combination therapy was 80% (16 of 20 subjects). The combination treatment group included 12 of 35 (34%) with two mood stabilizers and a stimulant; four of 35 (11%) with two mood stabilizers and an antipsychotic agent; and two of 35 (6%) with two mood stabilizers and an antidepressant agent. Twelve of 13 patients who had a stimulant added to their mood stabilizer(s) had a positive response on the CGI Improvement Scale for ADHD symptoms—an overall response rate of 92%. There were no serious adverse effects during the course of treatment with any of these subjects. In all cases, augmentation and combination treatment was well tolerated.
Discussion During the extension phase of treatment, 20 of 35 subjects (58%) required treatment with one or two mood stabilizers and either a stimulant, an atypical antipsychotic agent, or an antidepressant agent. The response rate to combination therapy was very good, with 16 of 20 subjects treated (80%) responding to combination therapy with two mood stabilizers after not responding to a single mood stabilizer during the acute phase of treatment. This suggests that children and adolescents with bipolar disorders are similar to adult bipolar patients, who also frequently require treatment with multiple medications (Frye et al 2000). The group that responded to treatment with a single mood stabilizer did not differ in any obvious way from the combination treatment in terms of past exposure to psychotropic medication, severity, age, or gender. Three of these 15 subjects were switched to another mood stabilizer before they became responders. This was usually done because they could not tolerate the initial mood stabilizer because of side effects. Only two subjects required the addition of an antidepressant agent for an episode of major depression. In both of these cases, an SSRI was added to the single mood stabilizer the subject was taking (lithium in one subject, divalproex in the other), with a good antidepressant response. This low rate of major depression may have been due to the fact that all of these subjects were treated aggressively with one or two mood stabilizers. Among adults with bipolar disorders, the use of mood stabilizers is thought to markedly lower the rate of major depressive episodes. The low rate of depressive episodes may also have been due to the relatively young age of our subjects (mean age of 11 ⫾ 2.9 years), as our clinical experience
Polypharmacy in Pediatric Bipolar Disorder
has been that major depressive episodes are more common once these bipolar patients reach adolescence. A significant proportion of these pediatric bipolar subjects required treatment of comorbid ADHD before they became improved in overall functioning—mood and attention. The typical clinical presentation was that of a prepubertal child who was diagnosed with ADHD at early age and subsequently treated with stimulants at approximately 4 –5 years of age. Then, usually at the age of 7– 8 years, the child’s bipolar symptoms would become very severe. In the majority of such cases, even after stimulant medications were discontinued, the child would continue to manifest severe mood lability and other bipolar symptoms. Once started on a mood stabilizer, their moods would improve, but they would continue to manifest ADHD symptoms. Our experience in this study was that the addition of a low-dose stimulant to this subject’s mood stabilizers would in many cases markedly improve the child’s ADHD symptoms without exacerbating the mood disorder. This finding runs against the prevailing clinical wisdom, which holds that stimulants may exacerbate manic symptoms in bipolar patients (DelBello et al 2001; Goodwin and Jamison 1990). Yet there are some reports that show this is not always the case in bipolar children and adolescents. Max et al (1995) reported an excellent response to dextroamphetamine in a 14-year-old male with an organic bipolar disorder. Our preliminary data, and those of others, indicate that children and adolescents with bipolar disorders frequently have comorbid ADHD that requires treatment in addition to their bipolar disorder. Our data and the data of others suggests that if a pediatric bipolar patient with comorbid ADHD is first stabilized on one or more mood stabilizers, then the addition of a stimulant is often very helpful in treating their comorbid ADHD (Biederman et al 1999). The critical issue appears to be the sequence of treatment, with the patient’s bipolar disorder treated before stimulant medication is added or reintroduced. This study is limited by its small sample size, the variable length of treatment during the acute phase, lack of a double blind, and lack of strict criteria for the addition of psychotropic agents. All of these subjects were outpatients, which limits the generalizability of these results to inpatient samples, for whom the severity and chronicity of the bipolar disorders is often greater. The long-term pharmacologic management of bipolar children and adolescents is often complicated by comorbid conditions, including ADHD, depression, and psychosis. The successful management of these patients frequently requires the use of combined mood stabilizers and other psychotropic agents. Further controlled studies of combination therapy are desperately needed in children and adolescents with bipolar disorders.
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Support is gratefully acknowledged from the National Alliance for the Mentally Ill/Stanley Foundation Research Awards Program and the National Institute of Mental Health, grant K07-MH01057 (RAK). WAW was funded by The Caleb C. and Julia W. Dula Education and Charitable Foundations, Mr. and Mrs. Woody Hunt, Mr. and Mrs. Morton Myerson, and the Azoulay Family. Aspects of this work were presented at the conference, “Pediatric Bipolar Disorder,” held March 9, 2002 in Boston, Massachusetts. The conference was sponsored by the Massachusetts General Hospital through and unrestricted educational grant provided by Janssen Pharmaceutica.
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