PART II COMORBID DISORDERS AND SPECIAL POPULATIONS Comorbid Disorders and Special PopulationsPharmacotherapy for ADHD and Mania CHAPTER 11 Pharmacotherapy for Attention-Deficit/Hyperactivity Disorder in Children with Mania KAREN DINEEN WAGNER Children with bipolar disorder frequently have comorbid attention- deficit/hyperactivity disorder (ADHD). The prevalence rates of comorbid ADHD and bipolar disorder in preschoolers has been reported to be 95% (Wilens et al., 2003) and as high as 98% in school-age children (Wozniak et al., 1995). Children with mania and ADHD have a more severe clinical course, including higher rates of psychosis, psychiatric hospitalization, and functional impairment, than children with ADHD alone. Furthermore, the clinical characteristics of ADHD in children with mania are severe, includ - ing a greater number of ADHD symptoms and higher rates of reading dis - ability than children with ADHD alone (Wozniak et al., 1995). Children with bipolar disorder and comorbid ADHD are often pre - scribed multiple medications. In a community sample of 111 children and adolescents with bipolar disorder, 56 (63%) had comorbid ADHD (Bhangoo et al., 2003). The mean number of medications used to treat these youths was 3.4, and the mean number of psychotropic medication trials in the past was 6.3. Of these youths, 98% had trials of a mood stabilizer/anticonvulsant, 76% had trials of an atypical antipsychotic, 68% had trials of a stimulant, and 76% had trials of a selective serotonin reuptake inhibitor (SSRI). 205 The medical records were reviewed for 83 children and adolescents with bipolar I disorder in a state mental health system (Jerrell & Shugart, 2004a). Of this sample, 83% received mood stabilizers, 40% received atyp - ical antipsychotics, 61% received antidepressants, and 28% received stimu - lants. Pharmacological treatment is often necessary to manage comorbid ADHD in children who have bipolar disorder. Because the age of onset of ADHD typically precedes the age of onset of bipolar disorder (Tillman et al., 2003), it is likely that children with bipolar disorder would have re - ceived stimulant treatment for ADHD. There is significant controversy about whether ADHD treatments, such as stimulants and antidepressants, will worsen mania in children with bipolar disorder. There are minimal controlled data to definitively resolve this controversy. However, case re - ports, chart reviews, open studies, and longitudinal follow-up provide some clinically useful information to address this issue. This chapter reviews available evidence on the question of whether pharmacological treatments for comorbid ADHD worsen the clinical course of mania in children with bipolar disorder. MEDICATION TREATMENT FOR COMORBID ADHD WORSENS MANIA: EVIDENCE BASE Case Reports There have been a number of case reports of stimulant-associated mania. A 10-year-old boy with ADHD and a positive family history for bipolar dis- order was treated with methylphenidate up to 45 mg/day by day 14 (Koehler-Troy, Strober, & Malenbaum, 1986). Between days 14 and 20, he developed a manic episode characterized by pressured speech, tangential thought, flight of ideas, severe hyperactivity, intrusiveness, belligerence, grandiose delusions, and sexually provocative comments. Methylphenidate was discontinued on day 24. Within 2 days, some improvement occurred in his condition. Treatment with lithium was initiated, with full remission of his manic symptoms. An 8-year-old boy with bipolar disorder had a history of dysphoria as - sociated with methylphenidate treatment and visual hallucinations associ - ated with dexedrine (Weller, Weller, & Dogin, 1998). A methylphenidate challenge induced manic symptoms (elevated mood, grandiosity, talkativeness, flight of ideas) in a 6-year-old boy suspected of having bipolar illness (Schmidt, Delaney, Jensen, Levinson, & Lewitt, 1986). Stimulant rebound that mimicked symptoms of bipolar disorder (irri - tability, anger, moodiness, insomnia, agitation, distractibility) was reported in a 7-year-old girl diagnosed with attention-deficit/hyperactivity disorder (Sarampote, Efron, Robb, Pearl, & Stein, 2002). 206 COMORBID DISORDERS AND SPECIAL POPULATIONS A 17-year-old boy with narcolepsy who was treated with modafinil 400 mg per day developed symptoms of mania—for example, flight of ideas, sexual excitation, and increased irritability (Vorspan, Warot, Consoli, Cohen, & Mazet, 2005). The modafinil was discontinued, and he devel - oped symptoms of sadness, anhedonia, and withdrawal. Modafinil was re - started, and the manic symptoms recurred. He required hospitalization and pharmacological treatment for mania. An 11-year-old boy with ADHD and a family history of bipolar disor - der was treated with atomoxetine (0.8 mg per kg per day; Henderson, 2004). After 3 weeks on atomoxetine treatment, his activity level in the classroom increased substantially, and there was no improvement in his at - tention. After 4 weeks, he developed marked oppositional and impulsive behavior at school. He threatened to kill a peer, was oppositional toward his teachers, and had a violent anger outburst in school. After 6 weeks, he developed insomnia and became increasingly irritable and violent, both at home and at school. At week 7, he had an angry outburst and brandished a sword at his family. He removed his clothes and covered his body with markings from a pen. Psychiatric hospitalization was necessary, and the atomoxetine was stopped. Within 7 days of atomoxetine discontinuation, the boy’s behavior returned to his baseline functioning. In the case histories of 9 children with mania, it was reported that stimulant treatment for ADHD worsened mania in those children who had family histories of bipolar disorder (Mota-Castillo et al., 2001). Case Series Henderson and Hartman (2004) pooled the data of 153 consecutive chil- dren (mean age 10.5 years old) treated with atomoxetine in outpatient set - tings. They reported that 51 (33%) children developed extreme irritability, aggression, mania, or hypomania. Of those individuals, 80% had a per - sonal history of mood symptoms, and 61% had a positive family history for mood disorders. Ten of these patients met diagnostic criteria for mania, and three of them were hospitalized. The onset of mood symptoms and/or aggression began at a mean of 6.4 weeks after starting treatment with atomoxetine. There was no difference in the time of onset of mood symp - toms between those patients who were also treated with mood stabilizers or atypical antipsychotics. Some of the patients were treated with stimulant augmentation, which reduced hyperactivity but not the irritability or ag - gression. Bhangoo et al. (2003) screened 111 youths by parent phone interview for potential inclusion in a study of bipolar disorder. Of these patients, 89 (80%) had a diagnosis of bipolar disorder, and 56 (63%) also met criteria for ADHD. Seventy-six (68%) of the children had a trial of a stimulant. The reported stimulant side effects and percentages were as follows: hyper - Pharmacotherapy for ADHD and Mania 207 activity (14%), irritability (9%), aggression (8%), decreased sleep (4%), and psychosis (1%). Eighty-seven (78%) of the youths had a trial of an SSRI. The reported SSRI side effects and percentages were as follows: hy - peractivity (9%), irritability (9%), aggression (9%), decreased sleep (3%), and psychosis (3%). Chart Review The medical records of 267 individuals (83 children and adolescents, 184 adults) with bipolar I disorder in a state mental health system were re - viewed (Jerrell & Shugart, 2004b). Compared with the adult patients, the child and adolescent patients were found to be more irritable, to have more functional impairment, to have made more suicide attempts, and to be more likely to be treated with stimulant medication and to meet criteria for major depression. There was no significant difference in treatment with mood stabilizers between children and adults. Given these age-related find - ings, the investigators postulated that treatment with stimulants may un- mask or trigger affective symptoms in youths. The medical records of 82 children with bipolar disorder were evalu- ated to assess treatment-emergent mania or increased mood cycling after pharmacological treatment (Faedda, Baldessarini, Glovinsky, & Austin, 2004). Treatment-emergent mania was found in 35 of 69 (50.7%) children who had been treated with a psychoactive agent. Of these cases, treatment- emergent mania was associated with use of a stimulant (24.2%) or an anti- depressant (75.7%). With regard to specific agents, the percentages of pa- tients with treatment-emergent mania were as follows: SSRIs, 48.7%; tricyclic antidepressant, 40.0%; other antidepressants, 30.7%; methylphenidate, 21.4%; amphetamines, 16.7%. The severity of bipolar disorder in hospitalized adolescents with a his - tory of stimulant or antidepressant treatment was assessed by Soutullo et al. (2002). In a retrospective chart review of 80 hospitalized adolescents with bipolar I disorder, manic or mixed, it was found that the lifetime rate of ADHD was 49%. Thirty-five percent of youths had been exposed to stimulants, and 44% had been exposed to antidepressants. The adolescents who had a history of stimulant exposure were younger than those who had no history of stimulant exposure (mean age = 13.7 years vs. 15.1 years). Adolescents with bipolar disorder who had histories of stimulant exposure had a more severe hospital course, defined by length of hospital stay, use of medication as needed, and need for seclusion and restraint. There was no difference in the hospital course between adolescents with or without ADHD. These investigators concluded that adolescents with bipolar disor - der who had prior treatment with stimulants may have a more severe course of illness that is not fully accounted for by comorbid ADHD. A comparison of the clinical characteristics of adolescents with bipolar 208 COMORBID DISORDERS AND SPECIAL POPULATIONS disorder with and without a history of stimulant treatment was conducted by DelBello et al. (2001). The sample consisted of 34 adolescents who were hospitalized for mania. Of these adolescents, 21 (62%) had histories of stimulant treatment. All of the adolescents who had prior stimulant expo - sure were initially treated with a stimulant before the onset of the affective episode. Eighty-two percent of the adolescents who were treated with stim - ulants were prescribed methylphenidate. The mean duration of stimulant exposure was 48 months. It was found that adolescents who had prior stimulant exposure had an earlier age of onset of bipolar disorder than those adolescents with no history of stimulant exposure (mean age = 10.7 years vs. 13.9 years). Furthermore, adolescents who had been treated with at least two stimulant medications in the past had a younger age of onset of bipolar disorder than those adolescents who had been treated with only one stimulant (mean age = 8.9 years vs. 12.7 years old). No significant cor - relation was found between the duration of stimulant treatment and the age of onset of bipolar disorder. There was no difference in the age of onset of bipolar disorder between those with and without ADHD. These investi- gators concluded that stimulant treatment, independent of ADHD, is asso- ciated with younger age of onset of bipolar disorder. These authors suggest that behavioral sensitization may account for their findings. They hypothe- size that children with a predisposition for developing bipolar disorder will experience increased frequency, severity, and duration of their affective symptoms when treated with stimulants. MEDICATION TREATMENT FOR COMORBID ADHD DOES NOT WORSEN MANIA: EVIDENCE BASE Case Reports A 12-year-old boy with ADHD and bipolar II disorder was treated with gabapentin, 200 mg per day, added to methylphenidate, 30 mg per day (Hamrin & Bailey, 2001). Mood stabilization was apparent within 3 weeks and continued at 6-month follow-up. A 14-year-old brain-injured adolescent with mania was successfully treated with dextroamphetamine after having failed prior trials of mood stabilizers (Max, Richards, & Hamden-Allen, 1995). Chart Review A chart review of pharmacological treatment was conducted for 38 chil - dren with bipolar disorder and comorbid ADHD (Biederman et al., 1999). It was found that improvement in ADHD required prior mood stabilization in these patients. The probability of improvement in ADHD symptoms was 7.5 times higher following initial improvement in manic symptoms than Pharmacotherapy for ADHD and Mania 209 was the probability of ADHD improvement prior to initial manic improve - ment. Treatment with tricyclic antidepressants, in the absence of mood sta - bilization, resulted in a relapse rate of 76% in the visits in which a tricyclic was taken compared with a 42% relapse rate in visits in which a tricyclic was not taken. A chart review was conducted of 42 hospitalized adolescents with bi - polar disorder who were treated with lithium or divalproex (State et al., 2004). Three of the 14 adolescents with bipolar disorder and comorbid ADHD were discharged on stimulant treatment concurrent with a mood stabilizer. Two of these adolescents were much or very much improved at discharge, and the third adolescent was minimally improved. The combina - tion of stimulant plus mood stabilizer did not worsen the clinical course of the bipolar illness in these 3 adolescents. Thirty-one preschoolers, ages 2–5 years old, with bipolar disorder were identified by chart review (Scheffer & Niskala Apps, 2004). Eighty percent of the children had comorbid ADHD. Twenty-one (68%) had had prior treatment with a stimulant or antidepressant, and, of these, 13 (62%) had worsening of mood symptoms. These children had not been on a mood stabilizer at the time of stimulant or antidepressant treatment. Twenty-six of the preschoolers were treated openly with a mood stabilizer, primarily valproic acid, over a 2-month to 2-year period, with a significant reduction in manic symptoms. Ten children received stimulant treatment for comorbid ADHD. None of these preschoolers experienced a worsening of mood symptoms when a mood stabilizer was administered concurrently with the stimulant. Open Studies Kowatch et al. (2000) conducted a 6- to 8-week acute treatment study in which 42 children and adolescents with bipolar I or II disorder were ran - domized to lithium, divalproex, or carbamazepine. Thirty-five of these youths participated in a 16-week open extension study (Kowatch, Seth - uraman, Hume, Kromelis, & Weinberg, 2003). During the extension phase, the treatment options for nonresponders were to switch mood sta - bilizer or augment mood stabilizer with another mood stabilizer, stimu - lant, antidepressant, or antipsychotic. Thirteen of these youths were treated with a mood stabilizer and a stimulant during the extension phase. Twelve (92%) showed clinical improvement (much or very much improved) of ADHD symptoms with the added stimulant. Importantly, there was no exacerbation of mood symptoms when the stimulant was added. A 1-month methylphenidate titration trial was conducted as part of a multimodal treatment study of children with ADHD. Of this sample, a sub - 210 COMORBID DISORDERS AND SPECIAL POPULATIONS set of 61 children with ADHD and some manic symptoms were identified (Galanter et al., 2003). Children received methylphenidate over the course of a 1-month trial. There was no difference in outcome measures between children with and without manic symptoms on measures of attention, impulsivity, and aggression. Importantly, there was no difference in adverse events such as irritability for children who received stimulants compared with those who did not receive stimulants. Acute Controlled Trials The effects of methylphenidate and lithium on attention and activity level were assessed by Carlson, Rapport, Kelly, and Pataki (1992). Seven hospi - talized children with both disruptive behavior disorders and bipolar disor - der or major depression were included in this study. Patients were crossed over with placebo, methylphenidate, lithium, and methylphenidate plus lithium. The lithium–methylphenidate combined-treatment group showed improved attention. Neither methylphenidate nor lithium exacerbated hy- peractivity. Methylphenidate, if used alone, worsened depression and irrita- bility in some children. The largest controlled study to date to assess whether adjunctive use of a stimulant is safe and efficacious for treating comorbid ADHD in children with bipolar disorder was conducted by Scheffer, Kowatch, Carmody, and Rush (2005). Forty children and adolescents, ages 6 to 17 years old, with bipolar I or II disorder and comorbid ADHD received 8-week open-label treatment with divalproex sodium. Thirty-two (80%) of the youths had a > 50% reduction in Young Mania Rating Scale (YMRS) scores from base- line to end point. Only three youths (.08%) showed significant improve- ment in ADHD symptoms. Thirty of the youths who were stabilized on divalproex entered a 2-week double-blind crossover trial of mixed amphet - amine salts or placebo. It was found that the mixed amphetamine salts were significantly more effective for ADHD symptoms than placebo. Im - portantly, there was no worsening of manic symptoms for children with bi - polar disorder who received mixed amphetamine salts. The investigators concluded that mixed amphetamine salts are safe and effective when added to divalproex sodium for the treatment of comorbid ADHD in pediatric bi - polar disorder. Longitudinal Studies A longitudinal study of stimulant treatment for children at risk for bipolar disorder was conducted by Carlson, Loney, Salisbury, Kramer, and Arthur (2000). Seventy-five boys, ages 6 to 12 years old, were diagnosed with hyperkinetic reaction and treated with methylphenidate. These boys were Pharmacotherapy for ADHD and Mania 211 [...]... SUD in particular and that adolescent-versus child-onset bipolar disorder confers a differential risk for SUD in adolescence in particular remain unclear Given the prominent genetic influences in both bipolar disorder and ADHD (as individual disorders and perhaps cosegregating), it remains unclear whether SUD in youths with bipolar disorder represent a subtype of bipolar disorder and/ or SUD or whether... SUD in bipolar disorder; and (6) bipolar disorder treatment over time may reduce the risk or attenuate the course of SUD Both family–genetic and self-medication influences may be operational in the development and continuation of SUD in adolescents and young adults with bipolar disorder; however, systematic data are lacking Patients with bipolar disorder and SUD require multimodal interventions incorporating... both short- and longterm effects on cognitive and neuropsychological functioning in adults (Block, 19 96) , although the extent of these findings in youths remains unclear Given the increasingly growing concern with neuropsychological and executive-function defects in predicting later SUD, children and adolescents with bipolar disorder, by nature of their multiplicity of cognitive deficits, are at independently... because (1) bipolar disorder is an increasingly recognized psychiatric disorder affecting children and adolescents although the course of the disorder is not well mapped out; (2) juvenile bipolar disorder generally has onset prior to SUD; (3) persistent bipolar disorder into adulthood is associated with SUD; (4) bipolar disorder is treatable; (5) bipolar disorder treatment results in reduced SUD in adolescents. .. role and interaction between bipolar disorder and CD in the context of SUD in youths remains relatively understudied Studies involving children with bipolar disorder and CD have documented a bidirectional link: a high overlap of CD in youths with bipolar disorder (Kovacs & Pollock, 1995; Wozniak, Biederman, Kiely, et al., Substance Use Disorders 221 1995; Faraone et al., 1997) and high rates of bipolar. .. Rate and predictors of prepubertal bipolarity during follow-up of 6- to 12-year-old depressed children Journal of the American Academy of Child and Adolescent Psychiatry, 33, 461 – 468 Geller, B., Zimerman, B., Williams, M., Bolhofner, K., & Craney, J L (2001) Adult psychosocial outcome of prepubertal major depressive disorder Journal of the American Academy of Child and Adolescent Psychiatry, 40, 67 3 67 7... disorder in at-risk individuals A 2-year follow-up study was conducted of 89 children and adolescents (mean age = 10.9 years) with a diagnosis of bipolar I disorder (Geller et al., 2002) Comorbid ADHD was present for 77 ( 86. 5%) of these children with bipolar disorder It was found that neither stimulant medication (administered to 53 participants; 59 .6% ) nor antidepressant medication (administered to 26 participants;... Lee Rosenberg, and Strakowski (2002) have shown specific executive functioning deficits in adolescents with bipolar disorder These findings in adolescents with bipolar disorder are of great relevance to the study of SUD given the link between academic and cognitive and neuropsychological dysfunction and 2 26 COMORBID DISORDERS AND SPECIAL POPULATIONS later SUD (Kellam, Brown, Rubin, & Ensminger, 1983;... phenomenology and treatment of youths and adults with bipolar I disorder in a state mental health system Journal of Affective Disorders, 80(1), 29–35 214 COMORBID DISORDERS AND SPECIAL POPULATIONS Koehler-Troy, C., Strober, M., & Malenbaum, R (19 86) Methylphenidate-induced mania in a prepubertal child Journal of Clinical Psychiatry, 47, 566 – 567 Kowatch, R A., Sethuraman, G., Hume, J H., Kromelis, M., & Weinberg,... bipolar disorder symptoms Semistructured psychiatric interviews are invaluable aids for the systematic diagnostic assessment of this group of patients Heavy, intermittent, binge use of substances is a tip-off to the possible existence of bipolar disorder in youth who are abusing substances The first consideration that clinicians should have in mind in the establishment of a specific treatment plan for adolescents . role and interaction between bipolar dis - order and CD in the context of SUD in youths remains relatively under - studied. Studies involving children with bipolar disorder and CD have docu - mented. potential inclusion in a study of bipolar disorder. Of these patients, 89 (80%) had a diagnosis of bipolar disorder, and 56 (63 %) also met criteria for ADHD. Seventy-six (68 %) of the children. controlling for CD. Our findings ap - peared to support the independence of both CD and bipolar disorder as in - dependent risk factors for adolescent-onset SUD. We are currently investi - gating