Letter to the Editor

Divalproex for the Treatment of AggressionAssociated with Adolescent Mania

Melissa P. DelBello, M.D., Caleb Adler, M.D., and Stephen M. Strakowski, M.D.

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JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGYVolume 14, Number 2, 2004© Mary Ann Liebert, Inc.Pp. 325–328

The Bipolar and Psychotic Disorders Research Program, University of Cincinnati College of Medicine, Departmentof Psychiatry, Cincinnati, Ohio.

BIPOLAR DISORDER is a common disorder, withonset typically occurring during adoles-

cence or early adulthood. In addition to themood instability and inattention associatedwith bipolar disorder, it is often characterizedby periods of aggressive behavior. Indeed, ag-gression is frequently the source of significantdiagnostic and treatment challenges, as well associal and functional impairment, suggestingthat the treatment of aggressive symptomsmay be an important component of an overalltherapeutic approach for patients with bipolardisorder (Swann 1999).

Treatment of adolescent bipolar disorder islikely to employ a range of pharmacologicalagents, which may be selected, in part, basedon the effectiveness for specific forms of illnessor against specific symptomatology (Swann1999). Divalproex has demonstrated effective-ness for the treatment of mania in children andadolescents (Kowatch et al. 2000; Wagner et al.2002). In addition, divalproex has shown ahigh rate of response in both an open-labelstudy and a placebo-controlled crossover studyof children and adolescents with disruptivebehavior disorders characterized by explosivetemper and mood lability (Donovan et al.1997; Donovan et al. 2000). However, to ourknowledge, there are no prospective studiesevaluating the effectiveness of divalproex for

the treatment of aggression associated with bi-polar disorder in youth.

With these considerations in mind, we per-formed a post hoc analysis of a prospectivestudy assessing the use of divalproex—aloneand in combination with quetiapine—for thetreatment of mania associated with bipolardisorder (DelBello et al. 2002), to determinewhether divalproex monotherapy was effec-tive for reducing aggression associated withmania. We hypothesized that divalproexwould be effective in reducing symptoms ofaggression and irritability.

Subjects for this study were recruited frominpatient admissions to the Adolescent Psy-chiatric Unit at Cincinnati Children’s Hospi-tal Medical Center during the period of May2000 through May 2001. Adolescents aged12–18 years, who were hospitalized for amanic or mixed episode, were eligible for thestudy if they met DSM-IV criteria for bipolardisorder, type I, currently mixed or manic,and had a Young Mania Rating Scale (YMRS)score of � 20 (Young et al. 1978; Fristad et al.1992). For complete inclusion and exclusioncriteria and study methods, please refer toDelBello et al. 2002. This study was approvedby the institutional review boards of the Uni-versity of Cincinnati and the Cincinnati Chil-dren’s Hospital Medical Center. Adolescent

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subjects provided written assent, and theirparents or legal guardians provided writteninformed consent for adolescent study partic-ipation after all the study procedures werefully explained.

The Washington University in St. Louis Kid-die Schedule for Affective Disorders andSchizophrenia (WASH-U-KSADS) was admin-istered to the subjects and their primary care-givers, in separate interviews, to confirm thediagnosis of bipolar disorder, type I (Gelleret al. 2001). All diagnostic interviews wereconducted by a trained rater (M.P.D.) whosediagnostic reliability with other experiencedinvestigators (� = 0.94) has been previously es-tablished (DelBello et al. 2002). Following theconfirmation of a diagnosis, subjects were ini-tiated on day 0 with 20 mg/kg/day of dival-proex; all subjects were titrated to atherapeutic serum level of 80–130 mg/dL byday 7. Subjects were maintained within thetherapeutic range until the study was termi-nated on day 42. Compliance was assessedusing pill counts and valproic acid serum levelassays during visits on days 3, 7, 14, 21, and 42.Each subject was also asked to maintain amedication log, to encourage compliance andtrack missed doses. Any patient who missed 2consecutive days of study medication was dis-continued from the study.

Each subject was assessed using the YMRS(Young et al. 1978; Fristad et al. 1992) and theChildhood Depression Rating Scale (CDRS)(Poznanski et al. 1979) at the baseline and onday 42 or at termination from the study; theoverall results from these assessments havebeen previously published (DelBello et al.2002). The primary effectiveness measures forthis report were changes from baseline to end-point in the irritability (score range 1–4) andaggression (score range 1–4) items from theYMRS, and in the irritability item from theCDRS (score range 1–7). Secondary efficacymeasures included changes from baseline toendpoint in the Positive and Negative Syn-drome Scale (PANSS) impulsivity item, and inthe PANSS hostility cluster (the mean of thePANSS anxiety, tension, hostility, suspicious-ness, uncooperativeness, and excitement itemscores, each item score range 1–7) (Kay et al.1989). A child and adolescent psychiatrist who

was blind to subject treatment status and withpreviously established reliability for each rat-ing scale (M.P.D.) completed all ratings by in-terviewing the subject and his or her primarycaregiver (intraclass correlation coefficient� 0.9). For each measure, the mean group dif-ference from baseline to endpoint was calcu-lated, and a paired samples t test was used totest for a significant overall group reduction inscore. For each variable, the assumption ofnormality was assessed and deemed reason-able, validating the results of the t test. All sta-tistical analyses were performed with theStatistical Analysis System for the PC (SAS In-stitute, Cary, NC, 1999).

Fourteen (14) of 15 adolescents with bipolardisorder who received divalproex monother-apy completed the 6-week treatment period.One (1) adolescent withdrew from the studyon day 14 because of the lack of effectivenessof the study medication in treating manicsymptoms. The mean age of participants was14.5 years (SD = ± 2 years). Seven (7) (47%) ofthe participants were female and 13 partici-pants (87%) were white. Most participants(n = 13, 87%) were admitted for a mixedepisode. Eight (8) subjects (53%) had a co-occurring diagnosis of attention deficit/hyper-activity disorder (ADHD), and psychosis waspresent in 7 (47%) of the adolescents. Meanvalproic acid level (measured throughout thestudy) was 102 mg/dL.

From baseline to endpoint, a significant re-duction was observed in scores for both theYMRS aggression (mean change ± SD, �0.9 ±2.0, p = 0.05) and irritability (mean change ±SD, �0.9 ± 1.0, p = 0.01) items. A significant re-duction was also observed in the irritabilityitem of the CDRS (mean change ± SD, �1.2 ±2.0, p = 0.02). A reduction was observed for11 of 15 subjects (73%) in the YMRS aggressionitem, for 11 of 15 subjects (73%) in the YMRS ir-ritability item, and for 12 of 15 subjects (80%)in the CDRS irritability item.

From baseline to endpoint, a statistically sig-nificant reduction was observed in the PANSSimpulsivity item score (mean change ± SD,0.72 ± 2, p = 0.04). In addition, a statisticaltrend toward a reduction of the PANSS hostil-ity cluster (mean change ± SD, �0.49 ± 1, p =0.07) was also demonstrated. The hostility clus-

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ter score was reduced in 9 of 15 subjects (60%).With regard to broader measures, statisticallysignificant reductions from baseline to end-point were observed in both the PANSS-posi-tive symptom subscale score (mean change ±SD, �5 ± 3, p = 0.002) and the overall YMRSscore (mean change ± SD, �14 ± 11, p = 0.002).

Aggression and violence contribute sub-stantially to morbidity for patients with bi-polar disorder (Posternak and Zimmerman2002). In children and adolescents with bipo-lar disorder, aggressive behavior may be as-sociated with psychiatric comorbidities or itmay be a manifestation of the disorder itself,in which case it may also lead to a mistakenattribution to a comorbidity or misdiagnosis(Biederman et al. 2000; Posternak and Zim-merman 2002).

Despite the functional impairment that mayoccur as a consequence of aggressive behav-iors in patients with bipolar disorder, fewstudies have specifically addressed the abilityof pharmacological therapy to attenuate ag-gressive symptoms associated with bipolardisorders. In an open-label case series, a low-dose risperidone treatment was associatedwith improvement in 8 of 11 children (aged5–16 years), with symptoms suggestive ofbipolar disorder, who had not responded ade-quately to mood stabilizers (Schreier 1998).

The results of the current analyses suggestthat divalproex is effective at reducing aggres-sive symptoms and behaviors associated withmania in adolescents with bipolar disorder.Statistically significant reductions were demon-strated in mean scores of standard assessmentitems for aggression, irritability, and impulsiv-ity. Indeed, we report a 25% reduction in theYMRS irritability and aggression items inmanic adolescents with bipolar disorder. Ourfindings were limited by the small sample size,a lack of a placebo control group, and singleitems on rating scales being used as the primaryefficacy measures. In addition, the exclusivefocus on the treatment of aggression associatedwith mania among hospitalized patients pre-vents any conclusions from being drawn as tothe effectiveness of divalproex in reducing ag-gression over longer periods of time, or in dif-ferent clinical samples. Finally, we were usingirritability items as a measure of aggression. Al-

though the anchors for the irritability item onYMRS includes degrees of aggressive behavior,such as “hostile and uncooperative,” future in-vestigations, ideally, should use an aggressionrating scale that would provide a directmeasure of aggression. Nonetheless, this pre-liminary study supports the need for larger,placebo-controlled studies of divalproex for thetreatment of aggression associated with bipolarand other psychiatric disorders that occur inadolescents and children.

ACKNOWLEDGMENT

This study was sponsored in part by a grantfrom Abbott Pharmaceuticals.

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Address reprint requests to:Melissa P. DelBello, M.D.

Caleb Adler, M.D.Stephen M. Strakowski

Department of PsychiatryUniversity of Cincinnati

231 Bethesda AvenueCincinnati, OH 45267-0559

E-mail: delbelmp@email.uc.edu

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