Primary Psychiatry. 2004;11(10):48-52
Faculty Affiliation and Disclosure
Dr. Lehman is a child and adolescent psychiatrist and geriatric psychiatrist in private practice and is director of PharmaSite Research, Inc., a clinical trial company conducting Phase II, III, and IV clinical trials for the treatment of psychiatric disorders, both in Baltimore, Maryland.
Disclosure: Dr. Lehman is a consultant for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Pfizer, and Sanofi-Synthelabo; is on the speaker’s bureaus of AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Pfizer, and Sanofi-Synthelabo; receives grant and/or research support from AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, GlaxoSmithKline, Merck, Pfizer, and Sanofi-Synthelabo; receives honoraria and/or expenses from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Pfizer, and Sanofi-Synthelabo; and is a major stock holder in Eli Lilly.
Funding/support: Preparation of this manuscript was funded by an unrestricted educational grant from Abbott.
Acknowledgments: The author wishes to thank Stacey C. Tobin, PhD, and Steve L. Apple, MD, for their assistance in the preparation of this manuscript. Information presented in this article was presented as an abstract at the American Psychiatric Association’s Institute of Psychiatric Services, October 29–November 3, 2003, in Boston, Massachusetts; and at the 16th Annual United States Psychiatric and Mental Health Congress, November 6–9, 2003, in Orlando, Florida.
Please direct all correspondence to: Robert B. Lehman, MD, PharmaSite Research, Inc., 1314 Bedford Ave, Ste 205, Baltimore, MD 21208; Tel: 410-602-0555; Fax: 410-602-1776; E-mail: email@example.com.
• Disruptive behaviors of children and adolescents are highly comorbid with multiple childhood psychiatric disorders and adversely impacted academic and social outcomes.
• Many medications are used to address the symptoms of behavior disorders in children, and polypharmacy is common in treating children and adolescents with the cluster of disruptive behavior symptoms.
• This study is a retrospective review confirming and extending the previous findings that disruptive behaviors in children and adolescents can be controlled with divalproex.
• Seventy-five percent of children exhibited improvement with divalproex and 50% demonstrated elimination of symptoms.
• The degree of responsiveness in subjects correlated with the treatment duration of divalproex.
Objective: Utilizing a retrospective review of 20 consecutive patients 5–18 years of age, this article evaluates the effectiveness of divalproex sodium (divalproex) in the management of disruptive behavior disorders in children and adolescents.
Method: Patients were treated with divalproex (average dose, 837.5 mg/day; range, 275–2,000 mg/day) for behavior dyscontrol in an outpatient psychiatric clinic. Subjects included in this review had unsatisfactory responses to previous pharmacotherapy. At followup, response to divalproex treatment was graded between 1 (no response) and 4 (elimination of disruptive behaviors) based on a global retrospective evaluation of improvement in behavior; these included changes in irritability, physical aggression, verbal aggression, and school-reported behavior disruptions.
Results: Of the 20 patients, 10 had grade 4 responses (very effective), 5 had grade 3 responses (moderately effective), 2 had grade 2 responses (mildly effective), and 3 had grade 1 responses (no response) to divalproex therapy. Adverse effects were mild and included weight gain, lethargy, and gastrointestinal distress.
Conclusion: These results confirm previous findings that divalproex is an effective pharmacotherapy for the control of disruptive behavior disorders in children and adolescents. These results warrant controlled, prospective studies to evaluate the use of divalproex in the treatment of pediatric populations with behavior dyscontrol.
Violence among children and adolescents has become a major social issue and public health problem in the United States.1 Aggressive behavior is associated with various neurologic conditions, including brain injury, developmental disorders, and dementia.2 In the pediatric population, violence and aggression may be a consequence of childhood disruptive behavior disorders, which cover a range of symptoms within such diagnostic categories as attention-deficit/hyperactivity disorder (ADHD), conduct disorder, oppositional defiant disorder (ODD), and bipolar disorder.3 The symptoms of disruptive behavior disorders range from irritability, impulsivity, and defiance to overt aggression directed at people, animals, and property.3 A recent study estimated that approximately 6% of school-age children have been diagnosed with ADHD,4 and there is extensive comorbidity of ADHD, ODD, conduct disorder, and bipolar disorder.5 If left untreated, disruptive behavior disorders can adversely impact academic and social development, and can lead to potentially dangerous or self-injurious behaviors.
There is no universally accepted pharmacotherapeutic approach to the treatment of disruptive behavior disorders, primarily because of inconsistent or vague definitions of antisocial behaviors and their biological and environmental bases.2 In addition, there have been few controlled trials that have addressed the benefits of pharmacotherapy for managing aggression or behavior dyscontrol in the pediatric population, leaving parents and physicians to face unknown risks of using untested pharmacotherapies to control potentially dangerous and destructive behaviors. Most treatment regimens include antidepressants; stimulants, such as methylphenidate and dextroamphetamine; lithium6,7; and antipsychotics to treat associated symptoms of depression and anxiety. Recent evidence suggests that anticonvulsant medications, including divalproex and carbamazepine, are also effective in the management of behavior dyscontrol, especially in patients who are not responsive to other classes of medication.8-10 To date, the efficacy of anticonvulsant therapy in the treatment of disruptive behavior disorders and aggression in children and adolescents has been studied in only a few small trials.
In one such trial, an open-label study of 10 children with conduct disorder, all but one patient showed statistically significant improvement with carbamazepine therapy (Global Clinical Consensus rating system, P<.005).11 However, in a 6-week, double-blind, placebo-controlled study of 22 children, carbamazepine did not significantly reduce aggression (Overt Aggression Scale, P>.5).12 Divalproex therapy improved temper and mood in 80% of children and adolescents diagnosed with ODD or conduct disorder in a 6-week, double-blind, placebocontrolled, crossover trial (Modified Overt Aggression Scale, P<.001).13 In addition, divalproex and another anticonvulsant, levetiracetam, have been shown to decrease aggression in children with autism,10,14,15 and several recent small controlled trials, studies, and case reviews have demonstrated the efficacy of divalproex and carbamazepine in controlling mania in children with bipolar disorder.16-19
This retrospective chart review was undertaken to further evaluate the effectiveness of divalproex in children and adolescents who were diagnosed with a range of disruptive behavior disorders and had responded poorly to previous pharmacotherapy.
The objective of this study was to evaluate the effectiveness of divalproex therapy in children and adolescents who were diagnosed with disruptive behavior disorders. The medical records of 20 patients who were sequentially assessed and treated for disruptive behavior disorders between January 1, 2000 and January 16, 2001 in an outpatient psychiatric clinic were reviewed. Each medical record was numerically coded to preserve patient privacy. A number of diagnostic categories were represented in addition to disruptive behavior disorders, and the full psychiatric diagnosis for each patient is given in the Table. Patients were diagnosed by a board-certified psychiatrist using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), diagnostic categories.3 During the study period, all patients were treated with divalproex (average dose, 837.5 mg/day; range, 275–2,000 mg/day) for 2 weeks. For a patient’s records to be eligible for review, his or her responses to previous pharmacotherapy had to be unsatisfactory (no improvement in irritability or physical or verbal aggression). Patients were excluded if inadequate data was available to render a complete retrospective evaluation of behavioral changes. Patient privacy was protected by removal of all identifying information from the chart prior to review.
The evaluation of the effectiveness of divalproex therapy was determined by a board-certified psychiatrist and was based on a global impression of behavior improvement over the treatment period. Changes in irritability, physical aggression, verbal aggression, and school-reported behavior disruptions were evaluated. Effectiveness was graded as 1 (ineffective, severe behavioral disturbances), 2 (mildly effective, moderate behavioral disturbances with some symptoms eliminated or symptoms reduced in intensity), 3 (moderately effective, mild behavioral disturbances with most symptoms eliminated or markedly reduced in intensity), and 4 (very effective, no behavioral disturbance). Adverse effects of treatment were also evaluated.
Of the 20 patients in the study, 13 were male and 7 were female. Patients ranged from 5–18 years of age, with a mean of 11 years of age (Table) and a median of 13 years of age. Most patients had more than one DSM-IV diagnosis. Diagnoses shared by six or more children were: attention-deficit disorder (ADD; n=10); ODD (n=11); major depressive disorder (n=7); and disorders of impulse control (n=6). Most patients had been treated previously with stimulant drugs (n=12), tricyclic antidepressants (n=7), or anticonvulsant drugs other than divalproex (n=6). Two patients had taken divalproex as part of a previous regimen without satisfactory response. When divalproex was reintroduced during the study period for these two patients, a higher dose was prescribed. Altogether, 59 medications (21 different drugs) were taken by patients before the initiation of divalproex therapy without satisfactory resolution of disruptive behavioral symptoms. A total of 21 medications (10 different drugs) were administered concomitantly with divalproex in 18 of 20 patients during the study period. Medications received with divalproex are listed in the Table for each patient. The length of divalproex therapy ranged from 2–98 weeks, with a mean treatment duration of 36 weeks. Average divalproex dose was 838 mg/day, and ranged from 375–2,000 mg/day.
Ten patients (50%) had grade 4 responses to divalproex, five (25%) had grade 3 responses, two (10%) had grade 2 responses, and three (15%) had grade 1 responses (Table). While divalproex was generally well tolerated, 12 patients (60%) reported mild adverse effects, including 6 cases of initial lethargy, 3 cases of modest weight gain, and 2 cases of gastrointestinal distress.
This retrospective case review confirms and extends previous findings by demonstrating that disruptive behaviors were controlled with divalproex in children and adolescents who did not respond to treatment with other anticonvulsant drugs, stimulants, or antidepressants. Seventy-five percent of patients in this study exhibited improvement with divalproex therapy, and all symptoms were eliminated in 50% of the patients reviewed.
The degree of response to divalproex treatment correlated with treatment duration. Ninety percent of patients with a grade 4 response received divalproex for 20–98 weeks, while all patients with a grade 3 response received divalproex for 24–80 weeks. In contrast, patients with mild or no response to divalproex received therapy for 2–6 weeks. This finding likely reflects the continued use of divalproex in those children for whom it was most effective.
Though the effect of divalproex therapy on improvement of behavior cannot be assessed independently from the effects of concomitant medication in the 15 children who received polypharmacy, there did not appear to be any association between improvement in behavior and concomitant drug use. Furthermore, patients receiving no concomitant medication had a range of responses to divalproex monotherapy, suggesting that other factors may influence the effectiveness of divalproex treatment (ie, coexisting disorders, dose, treatment duration, age, previous medication).
An assessment of the effect of concomitant medication timecourse was not performed in this study. Patterns of divalproex and concomitant medication administration may impact the effectiveness of divalproex in improving behavior control, and should be taken into account in future prospective studies. Finally, there was no correlation observed between maximum divalproex dose or blood levels and response to treatment.
It is significant that patients with a wide range of disruptive behavior disorders and associated disorders, including ADHD, ODD, depression, impulse control, explosive personality, and acute psychosis, responded well to divalproex therapy. However, the effectiveness of divalproex in treating behavior disorders in this study may be partially influenced by the presence of comorbid psychiatric disorders. Large-scale, controlled studies are required to assess the impact of multiple disorders on the efficacy of anticonvulsants in treating behavior dyscontrol.
The two patients with the most severe disruptive behavior disorder, conduct disorder, did not respond as well to divalproex as did patients with other behavior disorders. Previous studies have shown that the anticonvulsant carbamazepine also has variable effects on controlling aggression and explosive outbursts in children with conduct disorder.11,12 These observations raise the possibility that anticonvulsants have variable efficacy in the treatment of certain disruptive disorders. Indeed, a recent study suggested that a subset of children with disruptive behavior disorders who exhibited outer-directed irritability (aggression aimed at their environment but not at themselves) were particularly responsive to divalproex therapy.13,20,21 Furthermore, the anticonvulsants may have different effects on behavior dyscontrol in adult populations than in pediatric populations. For example, gabapentin has been effective in treating aggression and agitation in adult patients with dementia,22 but has been reported to exacerbate aggressive behaviors in children.23-25
Importantly, two of the most common adverse effects of divalproex therapy, lethargy and gastrointestinal distress, were mild and transient in this study, consistent with observations commonly reported for adult populations treated with valproate compounds.26,27 Weight gain, another frequent side effect of divalproex and sodium valproate therapy reported in previous studies,26 was sustained during treatment of the three children in whom it occurred. In contrast, previous studies of carbamazepine therapy in children with disruptive behavior disorders have reported transient fatigue, blurred vision, dizziness, rash, leukopenia, and diplopia.11,12
The majority of evidence supporting the efficacy of anticonvulsants, specifically divalproex and carbamazepine, in the treatment of bipolar disorder and other aggressive disruptive behaviors in children and adolescents consists of clinical opinion, case reports, and small trials.11-13,16-18,21,28,29 In this small study, introduction or addition of divalproex resulted in improvement in behavior in 75% of patients and the elimination of symptoms in 50% of patients, with only mild or transient adverse effects. Though this study was limited by its retrospective nature, use of the clinician’s retrospective impression of improvement, and small sample size, it confirms previous findings that divalproex is an effective pharmacotherapeutic alternative for treating behavior dyscontrol in children and adolescents. This chart review was not designed to demonstrate the superiority of divalproex over other medications, yet it provides further justification for conducting large-scale, controlled, prospective studies on the use of anticonvulsants to control disruptive behavior disorders in the pediatric population. Until such studies are conducted, small-scale, retrospective case reviews, such as this one, continue to provide support for the use of divalproex in treating children and adolescents with a number of psychiatric disorders involving behavior dyscontrol. PP
1. Pratt HD, Greydanus DE. Adolescent violence: concepts for a new millennium. Adolesc Med. 2000;11(1):103-125.
2. Ryan JM. Pharmacologic approach to aggression in neuropsychiatric disorders. Semin Clin Neuropsychiatry. 2000;5(4):238-249.
3. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994
4. Lesesne CA, Visser SN, White CP. Attention-deficit/hyperactivity disorder in school-aged children: association with maternal mental health and use of health care resources. Pediatrics. 2003;111(5 part 2):1232-1237.
5. Biederman J, Newcorn J, Sprich S. Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Am J Psychiatry. 1991;148(5):564-577.
6. Malone RP, Delaney MA, Luebbert JF, Cater J, Campbell M. A double-blind placebo-controlled study of lithium in hospitalized aggressive children and adolescents with conduct disorder. Arch Gen Psychiatry. 2000;57(7):649-654.
7. Campbell M, Adams PB, Small AM, et al. Lithium in hospitalized aggressive children with conduct disorder: a double-blind and placebo-controlled study. J Am Acad Child Adolesc Psychiatry. 1995;34(4):445-453. Erratum in: J Am Acad Child Adolesc Psychiatry. 1995;34(5):694.
8. Barratt ES. The use of anticonvulsants in aggression and violence. Psychopharmacol Bull. 1993;29(1):75-81.
9. Lindenmayer JP, Kotsaftis A. Use of sodium valproate in violent and aggressive behaviors: a critical review. J Clin Psychiatry. 2000;61(2):123-128.
10. McDougle CJ, Stigler KA, Posey DJ. Treatment of aggression in children and adolescents with autism and conduct disorder. J Clin Psychiatry. 2003;64(suppl 4):16-25.
11. Kafantaris V, Campbell M, Padron-Gayol MV, Small AM, Locascio JJ, Rosenberg CR. Carbamazepine in hospitalized aggressive conduct disorder children: an open pilot study. Psychopharmacol Bull. 1992;28(2):193-199. Erratum in: Psychopharmacol Bull. 1992;28(3):220.
12. Cueva JE, Overall JE, Small AM, Armenteros JL, Perry R, Campbell M. Carbamazepine in aggressive children with conduct disorder: a double-blind and placebo-controlled study. J Am Acad Child Adolesc Psychiatry. 1996;35(4):480-490.
13. Donovan SJ, Stewart JW, Nunes EV, et al. Divalproex treatment for youth with explosivetemper and mood lability: a double-blind, placebo-controlled crossover design. Am J Psychiatry. 2000;157(5):818-820. Erratum in: Am J Psychiatry. 2000;157(6):1038. Am J Psychiatry. 2000;157(7):1192.
14. Hollander E, Dolgoff-Kaspar R, Cartwright C, Rawitt R, Novotny S. An open trial of divalproex sodium in autism spectrum disorders. J Clin Psychiatry. 2001;62(7):530-534.
15. Rugino TA, Samsock TC. Levetiracetam in autistic children: an open-label study. J Dev Behav Pediatr. 2002;23(4):225-230.
16. Kowatch RA, Suppes T, Carmody TJ, et al. Effect size of lithium, divalproex sodium, and carbamazepine in children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2000;39(6):713-720.
17. Wagner KD, Weller EB, Carlson GA, et al. An open-label trial of divalproex in children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2002;41(10):1224-1230.
18. Davanzo P, Gunderson B, Belin T, et al. Mood stabilizers in hospitalized children with bipolar disorder: a retrospective review. Psychiatry Clin Neurosci. 2003;57(5):504-510.
19. Findling RL, McNamara NK, Gracious BL, et al. Combination lithium and divalproex sodium in pediatric bipolarity. J Am Acad Child Adolesc Psychiatry. 2003;42(8):895-901.
20. Donovan SJ, Nunes EV, Stewart JW, et al. “Outer-directed irritability”: a distinct mood syndrome in explosive youth with a disruptive behavior disorder? J Clin Psychiatry. 2003;64(6):698-701.
21. Donovan SJ, Susser ES, Nunes EV, Stewart JW, Quitkin FM, Klein DF. Divalproex treatment of disruptive adolescents: a report of 10 cases. J Clin Psychiatry. 1997;58(1):12-15.
22. Hawkins JW, Tinklenberg JR, Sheikh JI, Peyser CE, Yesavage JA. A retrospective chart review of gabapentin for the treatment of aggressive and agitated behavior in patients with dementias. Am J Geriatr Psychiatry. 2000;8(3):221-225.
23. Wolf SM, Shinnar S, Kang H, Gil KB, Moshe SL. Gabapentin toxicity in children manifesting as behavioral changes. Epilepsia. 1995;36(12):1203-1205.
24. Lee DO, Steingard RJ, Cesena M, Helmers SL, Riviello JJ, Mikati MA. Behavioral side effects of gabapentin in children. Epilepsia. 1996;37(1):87-90.
25. Tallian KB, Nahata MC, Lo W, Tsao CY. Gabapentin associated with aggressive behavior in pediatric patients with seizures. Epilepsia. 1996;37(5):501-502.
26. Redenbaugh JE, Sato S, Penry JK, Dreifuss FE, Kupferberg HJ. Sodium valproate: pharmacokinetics and effectivensss in treating intractable seizures. Neurology. 1980;30(1):1-6.
27. Bruni J, Wilder BJ. Valproic acid. Review of a new antiepileptic drug. Arch Neurol. 1979;36(7):393-398.
28. Papatheodorou G, Kutcher SP. Divalproex sodium treatment in late adolescent and young adult acute mania. Psychopharmacol Bull. 1993;29(2):213-219.