Therapy in Disruptive Behavior Disorders

Efficacy of Pharmacotherapy in Disruptive Behavior Disorders

 An Evidence Based Medicine Review

 Todd M. Felix

 Penn State College of Medicine

2004

 

Introduction

 

The Disruptive Behavior Disorders are the most common psychiatric disorder of childhood, with a prevalence of 4-9% of the entire pediatric population. The incidence is particularly high in patients with below average IQ, approximately 3-4 times more common than in children with normal IQ. There are often comorbid psychiatric diagnoses, including mood disorders, substance abuse, and ADHD. It is estimated that approximately two-thirds of children with ADHD will also have a disruptive behavior disorder diagnosed. The Disruptive Behavior Disorders can be classified according to DSM-IV into conduct disorder, oppositional defiant disorder, and disruptive behavior, NOS (18,19).

 

1. I. Conduct Disorder — A repetitive and persistent pattern of behavior in which the basic rights of others or major age-appropriate societal norms or rules are violated, as manifested by the presence of three or more of the following criteria in the past 12 months, with at least one criterion present in the past 6 months:

• Aggression to people and animals
• Destruction of property
• Deceitfulness or theft
• Serious violations of rules

The disturbance in behavior causes clinically significant impairment in social, academic, or occupational functioning, and criteria is not met for antisocial personality disorder if the patient is 18 years of age.

 

1. II. Oppositional Defiant Disorder (ODD) — A pattern of negativistic, hostile, and defiant behavior lasting at least 6 months, during which four or more of the following are present:

• Often loses temper
• Often argues with adults
• Often actively defies or refuses to comply with adults’ requests or rules
• Often deliberately annoys people
• Often blames others for his or her mistakes or misbehavior
• Is often touchy or easily annoyed by others
• Is often angry and resentful
• Is often spiteful or vindictive

The disturbance in behavior causes clinically significant impairment in social, academic, or

occupational functioning.

The behaviors do not occur exclusively during the course of a Psychotic or Mood Disorder

Criteria are not met for Conduct Disorder or Antisocial Personality Disorder(if older than 18)

 

III. Disruptive Behavior Disorder, NOS — This category is for disorders characterized by conduct or oppositional defiant behaviors that do not meet the criteria for Conduct Disorder or Oppositional Defiant Diorder.

 

 

Evidence Based Medicine    

 

1. Lithium carbonate – naturally occurring salt with mood altering properties; FDA approved for the treatment of Bipolar disorder, type I.

• Mechanism of action; Block inositol second messenger system, decrease 5-HT1a receptors, inhibits adenyl cyclase, increases Beta and alpha2 receptors, and increases dopamine in the tuboinfundibular system
• Usual pediatric dose 30mg/kg/dose twice daily
• Therapeutic blood level 0.6-1.2 mEq/L
• Follow BUN/Cr, TSH, and Ca regularly
• Adverse effects; Nausea, diarrhea, acne, abdominal ache, sedation, tremor, polydipsia, polyuria
• Drug interactions; SSRI, Antipsychotics, Antibiotics, NSAIDs (14)

 

à Until 1999-2000, there had been 4 double blind placebo controlled studies done in children to determine the antiaggressive effect of Lithium carbonate in the treatment of conduct disorder. Two trials showed statistically significant benefit, while two did not (10). A larger of theses studies looking at 50 hospitalized children aged 5-12 with aggressive type conduct disorder found 68% improvement in the Lithium group versus 40% improvement in the placebo group. Marked improvement was noted in 40% of patients treated with Lithium versus 4% given placebo (11).

 

A Double Blind Placebo Controlled Study of Lithium in Hospitalized Aggressive Children and Adolescents With Conduct Disorder (1)

 

• Six week study of patients ages 10-17 admitted to for severe aggression, and diagnosed with conduct disorder as per DSM-III-R.
• Randomized, double-blind, placebo-controlled trial with parallel group design and an initial 2 week single blind placebo period
• Scales used for initial evaluation and comparison of groups included Overt Aggression Scale (OAS), Clinical Global Impressions (CGI), and the Global Clinical Judgements Consensus Scale (GCJCS)
• 40 patients met criteria and were included into study, with initial general medical evaluation, vitals, height, weight, CBC, LFT, TSH, electrolytes, U/A, EKG, and pregnancy test if applicable
• 20 patients started on 600mg/d Li2CO3, and increased by 300mg/d to reach blood level 0.8-1.2. 20 patients were kept on placebo

Outcome as measured by:           Lithium                 Placebo

GCJCS                           16/20 improved           6/20 improved

CGI                               14/20 improved           4/20 improved

OAS                             -2.4 from baseline       -1.17 from baseline

 

Adverse effects: Nausea (12 v. 5), vomiting (11 v. 4), and urinary frequency (11 v. 4) occurred more in the treatment group than with placebo. Weight gain was not significantly different than placebo, with 1.9kg (17) vs. 1.6kg (16), respectively. There was one episode on asymptomatic elevation of LFT with lithium and no abnormalities in vital signs.

 

1. Valproic Acid – FDA approved for partial complex seizures, migraine, and manic episodes

• Mechanism of action; potentiation of GABAergic function in neurons
• Pediatric dosing 15mg/kg/day divided in 2-3 doses
• Therapeutic blood level 50-60ug/mL
• Check LFT and CBC on regular basis (6-12 months)
• Adverse effects; nausea, increased appetite, wgt gain, sedation, thrombocytopenia, alopecia, tremor, vertigo, polycystic ovaries
• Drug interactions; SSRI, Sedatives, Carbamazepine, lamotrigine (14)

à An earlier open trial of VPA in 10 adolescents with chronic temper outbursts and mood lability showed 100% response to initiation of medication (10).

 

Divalproex Treatment for Youth with Explosive Temper and Mood Lability: A Double-Blind, Placebo Controlled Crossover Design (2)

 

• 20 children with DSM-IV diagnosis of ODD or CD plus the following criteria; explosive temper, mood lability, sx greater than one year, impairment in 2 or more areas of life, not secondary to substance use, and not limited to a particular person or place.
• Randomized, double blind, placebo controlled study with crossover after 6 weeks of treatment for another 6 weeks
• Behavior and response to therapy were assessed by OAS and anger hostility subscale of SCL-90
• 10 patients were tapered to a VPA dose of 10mg/lb/d over the first 2 weeks.     Dosing was then changed by 250mg/d accordingly (Final dosing 750-1500 mg/d)
• Target blood level > 90ug/mL after 2 weeks

Outcome               Initial                              Crossover                  Adverse effects

Valproic acid         8/10 improved                   6/7 improved             Increase appetite (20%)

 

Placebo                   0/10 improved                  2/8 improved

 

 

III. Carbamazepine – FDA approved for partial/complex, generalized, and mixed seizures, as well as trigeminal neuralgia

• Mechanism of action; Tricyclic anticonvulsant that inhibits cAMP
• Dosing ages 6-12=100mg BID, ages >12=100mg TID
• Therapeutic blood level 8-11mg/mL
• Regularly check CBC and LFT
• Adverse effects; sedation, ataxia, dizziness, blurry vision, nausea, vomiting, and rarely hepatotoxicity and agranulocytosis
• Drug interactions; Lithium, SSRI, VPA, sedatives, TCA, lamotrigine (14)

 

à Three double blind controlled studies in the early 1970’s with patients exhibiting aggressive behavior showed 71% improvement with carbamazepine versus 26% improvement with placebo. Of note, most of these patients had abnormal EEG’s (10).

 

Carbamazepine in Aggressive Children with Conduct Disorder: A Double Blind and Placebo Controlled Study (6)

 

• Randomized double blind placebo controlled trial involving 24 children ages 5-12, who were hospitalized for explosive aggressiveness, and were diagnosed with CD as per DSM-III.
• A 2 week washout period was followed by a 6 week trial of Tegretol 200mg/d divided TID versus placebo. The Tegretol dose was increased by 200mg to a max of one gram in order to reach therapeutic blood levels of 4.9 to 9.1ug/mL. The average dose was 400-800 mg/d
• Outcome was measured by OAS, CGI, and CPRS (Children Psychiatric Rating Scale)
• 12 patients received carbamazepine and completed the study, 11 received placebo
• There was NO significant change in any of the hostility or aggression scales above between carbamazepine and placebo
• Adverse effects were common, but not noted if significantly different than placebo: Leukopenia, transient (6 drug vs. 0 placebo), weight gain of approximately 2 kg (10 vs. 6), and weight loss (2 vs. 3).
• Other potential adverse effects that were noted in this and previous studies include rash, drowsiness, psychosis, ataxia, diplopia, vertigo, and elevated LFT

 

1. Risperidone – Atypical antipsychotic used in the management of schizophrenia. It has also found use in the treatment of Tourette’s syndrome, bipolar disorder, autism, and aggressive behavior (12).

 

• Mechanism of action; serotonin and dopamine receptor antagonist, binding to 5HT-2 receptors greater than to D2 receptors.
• Adverse effects; sedation or insomnia, weight gain, extrapyramidal symptoms, orthostatic hypotension, hyperprolactinemia, anticholinergic symptoms, and prolongation of the QTc

 

à Two double blind, placebo-controlled trials and one open labeled trial of risperidone in the treatment of children with disruptive behavior disorder have been conducted. All showed significant reductions in aggressive behavior compared to placebo (3).

 

à A recent open labeled trial of risperidone in children with ADHD, CD, and ODD via DSM-IV criteria was completed. Patients were followed for 8 weeks, started on 0.25-0.5 mg of Risperdal, with an average dose of 1.27mg. 16/20 (80%) patients showed significant improvement as measured by the CGI (5).

 

à Reports from an ongoing study in England looking at children with ADHD and ODD or CD note benefit from Risperdal at doses 0.5 to 6mg. These patients were on stimulants and had usually failed clonidine. Most common adverse effect was weight gain in 10% of subjects (4).

 

Double-Blind, Placebo-Controlled Study of Risperidone for the Treatment of Disruptive Behaviors in Children with Subaverage Intelligence (3)

 

• 118 children ages 5-12 with DSM-IV Axis I diagnoses of ODD, CD or Disruptive Behavior NOS and Axis II diagnosis of subaverage intelligence (IQ 36-84)
• 6 week trial involving 11 centers, patients were assessed by Nissonger Child Behavior Rating Form, Abberant Behavior Checklist, and CGI
• Patients were permitted to continue stimulants through the study. Prolactin, GH, and routine lab tests were checked at onset and conclusion of study.
• Risperdal was started in 55 patients at a dose of 0.01mg/kg/d for 2 days, then 0.02mg/kg/d to max of 0.06mg/kg/d. The average dose was 1.16mg/d. 43 patients completed the 8 wk trial. 44 of 63 patients started on placebo completed the trial. Ineffectiveness, noncompliance and adverse effects were the most common cause for dropout
• Children treated with risperidone had significantly improved Nissonger Conduct scores (9.6 v 4.2) and CGI (77% v 33%).
• Adverse effects                 Risperdal (%)                 Placebo (%)

Somnolence                          51                                   10

Headache                             29                                   14

Vomiting                               20                                   6

Dyspepsia                           15                                     6

Weight gain                          15                                     2

Hyperprolactin                     13                                   2

Increased appetite                11                                     6

Rhinitis                                 11                                    5

No increase in serious side effects, cognitive impairments, QTc prolongation, or extrapyramidal symptoms.

 

1. Stimulants, Clonidine, and others

 

à A double blind study was conducted of 83 children ages 6-15 years with DSM-III criteria for CD and ADHD, randomized to receive Methylphenidate or placebo for the 3 year study. MPH was titrated to 60mg/d, with an average dose of 41mg/d (7).

• Behavior scales, as the Conners scale, were completed by teachers, parents, and psychiatrist throughout the study. The treatment group showed significant improvement in disruptive behavior, physical aggression, and problem free behavior. Did not show improvement in social aggression.
• Adverse effects of decreased appetite and insomnia were more common in the treatment group (84% v 46%)
• Conclusion of the study is that impulsivity is a key pathologic abnormality in both ADHD and CD

 

à A blinded study was conducted of 24 children ages 6-16 years with diagnosis of ADHD and ODD or CD, randomized to receive clonidine, methylphenidate, or combination of both for the 3 month study (9).

• Methylphenidate and clonidine doses were titrated to a maximum dose of 40mg/d (divided BID) and 0.3mg/d (divided TID), respectively.
• Outcome measures included a disruptive behavior scale completed by parents and teachers. All 3 groups showed similar improvements in ODD and CD symptoms.
• Patients taking combination had higher incidence of bradycardia than clonidine alone (50% v 25%). There was occasional lengthening of the PR interval in 7.9% patients taking combination and 4.4% taking clonidine. One other adverse effect noted was decreased fine motor activity, more common in the clonidine group

 

à An blinded Australian study was conducted on 67 white children with DSM-IV diagnoses of ADHD and ODD or CD already on a stimulant. Patients were randomized to receive clonidine syrup or placebo for 6 weeks (8).

• Clonidine dosing was started at 0.05mg/d and increased after one week to 0.10mg/d – 0.20mg/d
• Outcome was assessed by Conduct and Hyperactive Index Subscales of Conners Behavior Checklist. Significant improvement was seen with respect to conduct scores (57% v 21%) and non-significant improvement was seen when assessing hyperactivity (35% v 17%).
• Adverse effects in the treatment group included drowsiness and dizziness. Surprisingly, improvements in the following were seen in the treatment group; irritability, crying, anxiety, interest, headaches, and talking with others.

à Very few and small studies have looked at antidepressants in the management of disruptive behavior disorders in children.

• An open trial of trazadone in children with ODD or CD showed effectiveness in treating aggressive symptoms (15).
• A study looking at the effect of desipramine in children with diagnosis of ADHD and either CD or ODD. Improvements in attention, hyperactivity, and aggressive behavior were seen in the group taking desipramine + MPH, more so than each drug individually or placebo (16).
• Serotonergic receptors, specifically 5-HT 1B/1D, are suggested to be more sensitive in children with ODD.

à Neurontin is a fairly new medication used as a mood stabilizer, but has been shown to cause behavioral disinhibition in children.

àLamictal is also a new medication indicated as a mood stabilizer, but is not recommended for children less than 16 years, secondary to concerns about a Stevens Johnson rash (14).

à The effects of behavioral modification cannot be overemphasized as a critical adjuvant in the treatment of children with Disruptive Behavioral Disorders (13).

 

 

References:

 

• 1) Malone, R et al. A Double-Blind Placebo-Controlled Study of Lithium in Hospitalized Aggressive Children and Adolescents With Conduct Disorder. Arch Gen Psychiatry. July 2000; 57(7): 649-54.
• 2) Donovan, S. J. et al. Divalproex Treatment for Youth With Explosive Temper and Mood Lability: A Double-Blind, Placebo-Controlled Crossover Design. Am J Psychiatry. May 2000; 157(5): 818-820.
• 3) Aman, M. G. et al. Double-Blind, Placebo-Controlled Study of Risperidone for the Treatment of Disruptive Behaviors in Children With Subaverage Intelligence. Am J Psychiatry. Aug 2002; 159(8): 1337-1346.
• 4) Kewley, Geoffrey. Risperidone in comorbid ADHD and ODD/CD. J Am Acad Child Adolesc Psychiatry. Nov 1999; 38(11): 1327-8.
• 5) Sabri Ercan, E. et al. Risperdone in children and adolescents with conduct disorder: A single center, open label study. Curr Ther Research, Clin & Exp. Jan 2003; 64(1): 55-64.
• 6) Cueva, J. E., et al. Carbamazepine in aggressive children with conduct disorder: A double-blind and placebo-controlled study. J Am Acad Child Adolesc Psychiatry. Apr 1996; 35(4): 480-90.
• 7) Klein, R. G., et al. Clinical Efficacy of Methylphenidate in Conduct Disorder With and Without ADHD. Arch Gen Psychiatry. Dec 1997; 54(12): 1073-80.
• 8) Hazel, Philip and John Stuart. A Randomized Controlled Trial of Clonidine Added To Psychostimulant Medication For Hyperactive And Aggressive Children. J Am Acad Child Adolesc Psychiatry. Aug 2003; 42(8): 886-94.
• 9) Connor, Daniel et al. A pilot study of methylphenidate, clonidine, or the combination in Pediatrics. Jan 2000; 39(1): 15-25.
• 10) Ryan, N. et al. Mood Stabilizers in Children and Adolescents. J Am Acad Child Adolesc Psychiatry. May 1999; 38(5): 529-36.
• 11) Campbell, Magda et al. Lithium in hospitalized aggressive children with conduct diorder: A double-blind an placebo-controlled study. J Am Acad Child Adolesc Psychiatry. Apr 1995; 34(4): 445-53.
• 12) Lexi-Comp. Risperdone: Pediatric drug information. UptoDate Online. 2004; 1-8
• 13) Kolko, D., Bukstein, O., and Jerome Barron. Methylphenidate and Behavior Modification in Children With ADHD and Conorbid ODD or CD: Main and Incremental Effects Across Settings. J Am Acad Child Adolesc Psychiatry. May 1999; 38(5): 578-85.
• 14) Kowatch, R. and John Bucci. Mood Stabilizers and Anticonvulsants. Peds Clinic of North America. Oct 1998; 45(5): 1173-86.
• 15) Ghaziuddin, N. and Norman Alessi. An open trial of trazodone in aggressive children. J Child Adolesc Psychopharmacology. Win 1992; 2(4): 291-97.
• 16) Carlson, Gabrielle et al. Methylphenidate and desipramine in hospitalized children with comorbid behavior and mood disorders: Separate and combined effects on behavior and mood. J Child Adolesc Psychopharmacology. Fal 1995; 5(3): 191-204.
• 17) Heddeke, S. et al. Serotonergic functioning in children with oppositional defiant disorder: a sumatriptan challenge study. Biological Psychiatry. Feb 2002; 51(4): 319-25.
• 18) Stead, L. et al. First Aid for the Psychiatry Clerkship. New York: McGraw-Hill, 2002.
• 19) Lewis, Melvin. Child and Adolescent Psychiatry: A comprehensive textbook. Baltimore: Williams & Wilkins, 1996.

Medline/PsychInfo search keywords: Disruptive Behavior Disorders (ODD/CD), Mood Stabilizers, and Children.   Limit to English and Human studies.