Risperidone Augmentation for Treatment-Resistant Aggression in Attention-Deficit/Hyperactivity Disorder: A Placebo-Controlled Pilot Study

doi:10.1097/chi.0b013e3180323354

Journal of the American Academy of Child & Adolescent Psychiatry

Volume 46, Issue 5, May 2007, Pages 558-565

https://doi.org/10.1097/chi.0b013e3180323354 Get rights and content

ABSTRACT

Objective:

To evaluate the effects of risperidone augmentation for treatment-resistant aggression in children with attention-deficit/hyperactivity disorder (ADHD).

Method:

Twenty-five children (ages 7-12 years) with attention-deficit/hyperactivity disorder (ADHD) and significant aggressive behaviors were randomized to risperidone or placebo for 4 weeks for this double-blind study. Subjects were already in treatment with a constant dose of psychostimulant medication. The primary efficacy measure was change from baseline in the Children's Aggression Scale-Parent (CAS-P) and -Teacher (CAS-T) total scores.

Results:

The mean risperidone dose at endpoint was 1.08 mg/day. For the CAS-P total score, a significant difference was found (χ²₁ = 4.30, p < .05) with 100% of risperidone subjects improving by more than 30% from baseline to endpoint, whereas only 77% of the placebo group reported a similar response. No differences were found on the CAS-T total score. For the CAS-P and CAS-T, no significant interaction was found between treatment group and time. Rates of adverse events did not differ significantly between groups.

Conclusions:

Risperidone treatment appears to be well tolerated and modestly effective when used in combination with psychostimulants for treatment-resistant aggression in children with ADHD.

Section snippets

METHOD

This study was a 28-day, double-blind, placebo-controlled trial of risperidone as an augmenting agent in children, 7 to 12 years of age, with ADHD. The study was conducted in accordance with the Declaration of Helsinki and was approved by the Human Subjects Research Office of the University of Miami Miller School of Medicine. Patients were required to provide assent before participation and the patient's parent or legal guardian had to provide written consent. A subject could withdraw from the

Patient Characteristics

Twenty-five subjects participated in the study, with 12 assigned to risperidone treatment and 13 assigned to placebo. No statistically significant differences were found for age, gender, race, weight, body mass index (BMI), Aggression Questionnaire Predatory-Affective index score, CAS-P total score, or CAS-T total score between the treatment groups at baseline (Table 1). Comorbid diagnoses were found in 16 subjects. These included oppositional defiant disorder (n = 13), conduct disorder (n =

DISCUSSION

This study is the first randomized, placebo-controlled, double-blind trial of risperidone augmentation for treatment-resistant aggression in children with ADHD. As a pilot study this trial was designed for hypothesis generation and not as a definitive test of efficacy. Results of this study do not provide convincing evidence that augmentation of stimulant treatment with risperidone in aggressive children with ADHD is an effective treatment strategy. Risperidone augmentation of psychostimulant

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Citation Excerpt :
Other research groups found individuals diagnosed with ADHD, who also displayed disruptive behaviors such as aggression (i.e., comorbid ADHD), had better outcome ratings when they augmented stimulant and behavioral treatment with antipsychotics (Aman et al., 2014). Some investigations, however, found either limited or no additional improvements in outcome measures with combination therapy (Armenteros et al., 2007; Findling et al., 2007). More recent studies have investigated potential physical reactions of combined stimulant and antipsychotic therapy, with some studies finding adverse responses (Schweren et al., 2015), and other studies showing either mixed results or no effects when compared to taking only one of the medication types (i.e., monotherapy; Bali et al., 2019; Linton et al., 2013).
Consistent with federal requirements for states to monitor psychotropic medication use in foster children and adolescents, we assessed prescribers’ adherence to best practice guidelines. Specifically, we identified the prevalence and patterns of combined use of stimulants and antipsychotics among a sample of foster children and adolescents that received additional non-pharmacological interventions from a state-funded team. A secondary purpose of this paper was to demonstrate a method for monitoring psychotropic medication use for this vulnerable population.
Using data from a state Medicaid database and a state-funded team, we tracked medication use among a sample of 128 foster children and adolescents aged 5–19 years with varying diagnoses who received behavioral and medication review services. We extracted data for children and adolescents who received the combination of stimulants and antipsychotics, and then we visually depicted the data to show changes in medication use before, during, and after our services.
Out of the larger sample, twenty-one foster children and adolescents (16%) simultaneously received stimulants and antipsychotics. Visual depictions of data show that less than 50% received stimulants alone before combined use. In addition, participants experienced limited changes in medication regimens even after receiving non-pharmacological services.
These findings suggest that prescribers may not adhere to practice guidelines for use of stimulants and antipsychotics, even for clients who receive other services, and highlight the need for relevant stakeholders to monitor unsafe prescribing practices.
The pharmacological treatment of aggression in children and adolescents with conduct disorder. Do callous—unemotional traits modulate the efficacy of medication?
2018, Neuroscience and Biobehavioral Reviews
Children and adolescents with conduct disorder (CD) show repetitive and persistent patterns of aggressive behaviour and the more severe forms are often associated with callous-unemotional (CU) traits.
To systematically review and, where data are adequate, conduct meta-analyses on the efficacy of medication on aggression in children and adolescent with CD considering the impact of CU traits.
Few studies have investigated patients with CD as primary diagnosis, and few of these have discriminated between different types of aggression or reported measures of CU traits. Methylphenidate and risperidone showed the largest effects on aggression in randomized controlled trials; other antipsychotics showed clinical efficacy on CD but this evidence is mainly revealed by open label trials. There is some low quality evidence to support a small effect of mood stabilizers and other agents. There were only two papers describing the effects of CU traits thus providing inconclusive results.
Considering heterogeneity of the disorder, more proof-of-concept clinical studies are needed to define effects of medication and role of CU traits.
Trends in Antipsychotic Prescribing in Medicaid-Eligible Youth
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To examine trends in the use of antipsychotic medication in Medicaid-eligible youth from 2008 to 2013 and the factors associated with this use.
Youth aged 0 to 17 years with at least one claim indicating antipsychotic medication use were identified from the network of a behavioral health managed care organization (BHMCO). Demographic and clinical variables were derived from state eligibility data and service claims data from the BHMCO. Overall and specific prevalence rates of antipsychotic drug use were calculated over the course of 6 years (2008−2013). The probability of antipsychotic use during 2013 was further explored with logistic regression that included demographic and diagnostic groups.
The overall trend in prevalence for antipsychotics for youth decreased from 49.52 per 1,000 members in 2008 to 30.54 in 2013 (p < .0001). Although rates decreased for all age groups, the rate per 1,000 members in 2013 for the youngest children was 3.79, versus 39.23 for 6- to 12-year-olds and 64.33 for 13- to 17-year-olds. Controlling for demographic and clinical variables, children 0 to 5 years old were 79% less likely to be prescribed antipsychotic medications compared to the oldest youth, 13 to 17 years of age (p < .0001). Rates were higher for males versus females regardless of age (odds ratio [95% CI] =1.48 [1.36−1.62], p < .0001). Children with a diagnosis of attention-deficit/hyperactivity disorder were less likely to be prescribed antipsychotics compared to those with diagnoses of autism spectrum disorder, bipolar disorder, psychoses, and depression.
Prevalence rates decreased significantly over time for all socio-demographic groups. The largest decrease was observed for the youngest children, ages 0 to 5 years, with a rate in 2013 under half the rate for 2008. Clinical, policy, and managed care implications are discussed.
Early antipsychotic exposure affects serotonin and dopamine receptor binding density differently in selected brain loci of male and female juvenile rats
2016, Pharmacological Reports
Antipsychotic drugs (APDs) were developed to treat schizophrenia in adults; however they have been increasingly prescribed (mostly “off-label”) for children and adolescents. This study aimed to investigate the effects of aripiprazole, olanzapine and risperidone on the binding of serotonin (5-HT) and dopamine receptors in juvenile rat brain regions that are involved in antipsychotic efficacy.
Male and female rats were treated orally with aripiprazole (1 mg/kg), olanzapine (1 mg/kg), risperidone (0.3 mg/kg) or vehicle 3 times/day starting from postnatal day 23 (±1 day) for 20 days. Quantitative autoradiography was performed to examine the receptor binding densities.
Olanzapine significantly decreased 5-HT_2A (5-HT_2AR) and 5-HT_2C receptor (5-HT_2CR) binding in the prefrontal cortex (PFC), cingulate cortex (Cg) and nucleus accumbens (NAc) of both male and female rats. In the caudate putamen (CPu), olanzapine attenuated 5-HT_2AR binding in both genders, and reduced 5-HT_2CR binding in male rats. Olanzapine increased D₂ receptor (D₂R) binding in the NAcS of male rats, but decreased it in females. Olanzapine increased D₁ receptor (D₁R) binding in the Cg, while aripiprazole decreased D₁R binding in the PFC of males. Aripiprazole significantly reduced 5-HT_2AR binding in the male PFC. Risperidone decreased 5-HT_2AR binding in the PFC of female rats, while attenuating D₁R binding in the PFC and Cg of males. However, APDs have no effects on the binding of serotonin and dopamine transporters.
This study revealed that aripiprazole, olanzapine and risperidone affected 5-HT_2AR, 5-HT_2CR, 5-HTT, D₁R and D₂R bindings differently in the brains of juvenile male and female rats.
The Use of Brexpiprazole Combined With a Stimulant in Adults With Treatment-Resistant Attention-Deficit/Hyperactivity Disorder
2022, Journal of Clinical Psychopharmacology

View all citing articles on Scopus

This study was supported by Janssen, LP.

Disclosure: Dr. Armenteros has received research support and is on the speakers' panel of Janssen Pharmaceutica. The other authors have no financial relationships to disclose.

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ARTICLESRisperidone Augmentation for Treatment-Resistant Aggression in Attention-Deficit/Hyperactivity Disorder: A Placebo-Controlled Pilot Study

ABSTRACT

Objective:

Method:

Results:

Conclusions:

Section snippets

METHOD

Patient Characteristics

DISCUSSION

The normalizing effects of methylphenidate on the classroom behavior of ADHD children

J Abnorm Child Psychol

Double-blind, placebo-controlled study of risperidone for the treatment of disruptive behaviors in children with subaverage intelligence

Am J Psychiatry

Attention-deficit hyperactivity disorder

Sci Am

Prevalence and assessment of attention-deficit/hyperactivity disorder in primary care settings

Pediatrics

Open-label treatment with risperidone of 26 psychiatrically-hospitalized children and adolescents with mixed diagnoses and aggressive behavior

J Child Adolesc Psychopharmacol

A randomized controlled trial of risperidone in the treatment of aggression in hospitalized adolescents with subaverage cognitive abilities

J Clin Psychiatry

Methylphenidate effects on a laboratory aggression measure in children with ADHD

Psychopharmacol Bull

Conners' Rating Scales: Revised Technical Manual

Psychopharmacology and aggression. I: A meta-analysis of stimulant effects on overt/covert aggression-related behaviors in ADHD

J Am Acad Child Adolesc Psychiatry

A double-blind pilot study of risperidone in the treatment of conduct disorder

J Am Acad Child Adolesc Psychiatry

Normative data on revised Conners parent and teacher rating scales

J Abnorm Child Psychol

Stimulant medications

J Am Acad Child Adolesc Psychiatry

ECDEU Assessment Manual for Psychopharmacology Revised (Publication ADM 76–338)

Reliability, validity, and preliminary normative data for the Children's Aggression Scale-Teacher Version

J Am Acad Child Adolesc Psychiatry

Development, reliability, and validity of the Children's Aggression Scale-Parent Version

J Am Acad Child Adolesc Psychiatry

ARTICLES
Risperidone Augmentation for Treatment-Resistant Aggression in Attention-Deficit/Hyperactivity Disorder: A Placebo-Controlled Pilot Study