Antipsychotic and Psychostimulant Drug Combination Therapy in Attention Deficit/Hyperactivity and Disruptive Behavior Disorders

Introduction

This systematic review examines treatment guidelines, efficacy/effectiveness, and tolerability regarding the concurrent use of antipsychotics with psychostimulants in treating aggression and hyperactivity in children and adolescents with comorbid ADHD and DBDs.
Combination therapy is recommended by some guidelines, but only as a third-line treatment.
Some studies suggest efficacy/effectiveness, but data do not clearly demonstrate superiority compared to monotherapy.
Most studies had short time periods, lacked blinding, or placebo control, and no comparisons were made with behavioral interventions.
There are concerns about tolerability, but data do not suggest significantly worse adverse effects compared to monotherapy.
Stimulant use does not significantly reduce metabolic effects of antipsychotics.
Few studies have directly examined this combination for the treatment of ADHD and DBDs, further studies are necessary.

Background

Prescription rates of antipsychotics have increased substantially in youth in the US, Canada, and Europe.
Polypharmacy with other psychotropics, especially psychostimulants, is becoming common, and many antipsychotics are being prescribed for off-label indications.
ADHD and DBDs (including ODD and CD) are now two of the most common diagnoses among those prescribed antipsychotics.
In a national study of US Medicaid-enrolled children between 2002 and 2007, by 2007, youth with ADHD made up 50% of all antipsychotic use; 13.8% of the antipsychotic users had ADHD as their only diagnosis.
Psychostimulant drug therapy is a specifically approved and widely accepted treatment for ADHD in young people.
The Texas Children’s Medicine Assessment Project’s (CMAP) guidelines recommend psychostimulants as the first-line therapy for ADHD, even with comorbidities.
Stimulants are highly effective and well-tolerated for ADHD, and are also effective for treating aggression in patients with comorbid ADHD.

Monotherapy

Numerous studies have shown that antipsychotics can be an efficacious monotherapy in young people for conditions including psychosis, bipolar disorder, and aggression.
Second-generation antipsychotics appear to be efficacious in the treatment of DBD.
Risperidone, quetiapine, aripiprazole, and olanzapine have been approved for use in adolescents (some by the FDA, some by Health Canada), but no antipsychotics are specifically approved for use to treat aggression in children in the US or Canada.
In children and adolescents, virtually all antipsychotic drugs prescribed are second-generation antipsychotics.
These drugs are associated with a decreased risk of EPS and tardive dyskinesia compared to first-generation antipsychotics, but an increased risk for metabolic side effects.
Children and adolescents treated with antipsychotics may develop side effects including EPS, weight gain, and hyperprolactinemia, and the risk of these side effects may be higher in children than adults.

Paradox of Combination Therapy

Both psychostimulant and antipsychotic monotherapy are supported by evidence for the treatment of ADHD and DBD; however, combining these two classes can seem paradoxical from a pharmacological perspective.
Antipsychotic drugs are antagonists at dopamine receptors, whereas psychostimulant drugs are indirect agonists and increase synaptic levels of dopamine and other monoamines.
This paradox is reconciled upon examination of the pharmacology of the receptor subtypes and brain regions responsible for mediating each of the effects.
Antipsychotic drugs antagonize dopamine receptors in a number of brain regions, but blockade of mesolimbic D2 receptors is principally responsible for the therapeutic actions.
The therapeutic actions of stimulants are thought to be due to the increased dopamine available in the synapse in the mesocortical dopamine system and a net downregulation of a hyperactive nigral-striatal dopamine system due to autoinhibition.
The “complex dopamine model” suggests that increased tonic dopamine release and decreased pulsatile release of dopamine can be produced by both psychostimulants and antipsychotics.
Based on this model, it has been hypothesized that antipsychotics and stimulants may even act synergistically, potentially allowing for lower doses, a decreased risk of developing tolerance, and reduction in adverse effects due to each respective class.
Combination therapy simultaneously raises concerns about potentially reducing the effectiveness of each drug, as well as hopes that combination therapy may be more effective than the sum of its parts.
Despite these uncertainties, these drugs are often used concomitantly for ADHD and DBD.
In a Canadian population-based study, the use of antipsychotics in combination with methylphenidate increased from 13% in 1999 to 43% in 2008.
There is a relative dearth of research regarding combination therapy with these two classes of drugs.
The intent of this review is to: (1) summarize/describe current guidelines and recommendations regarding the use of combination therapy, (2) present a systematic review of evidence for the efficacy/effectiveness of combination therapy, and (3) review the evidence for the tolerability associated with treating children and adolescents using the combination of a psychostimulant and an antipsychotic.

Methods

A literature search was performed on both the PubMed (1947 to 2012) and EMBASE (1974 to 2012) databases using the keywords: stimulant, antipsychotic or neuroleptic, combination, and children.
Records were screened based on inclusion criteria: (1) mean patient age less than 18 years, (2) DSM-IV diagnosis of ADHD, and (3) intervention involving combination of an antipsychotic and a psychostimulant.
Chart reviews and all studies published in languages other than English were excluded.
Reference lists from identified studies were reviewed for additional studies that might meet the inclusion criteria.
An additional search was conducted to identify treatment guidelines regarding the practice of antipsychotic and psychostimulant drug combination therapy using a PubMed search with the terms “guideline,” “aggression,” and “children”.

Guidelines Recommending Combination Therapy

Although combination therapy with antipsychotics and psychostimulants is not recommended as a first-line treatment, all identified guidelines and consensus statements recommend the use of combination therapy following the failure of other interventions, either in CD or in the treatment of more generally defined aggression.

International Consensus Statement (2004)

To treat patients with combined ADHD and CD, recommends first-line use of psychostimulants in combination with social behavior therapy and to add risperidone only after several weeks of an insufficient response at the maximum daily dose of stimulant and social behavior therapy.

Texas CMAP Group

Algorithm for the treatment of ADHD based on a consensus conference with experts, clinicians, and other stakeholders.
Recommendation for treatment of ADHD with comorbid aggression: first-line is psychostimulants in monotherapy, second-line is psychostimulants with behavioral therapy, and third-line recommends second-generation antipsychotics in combination therapy with psychostimulants.
Acknowledges that this recommendation is largely based on the efficacy of second-generation antipsychotics as monotherapy in the treatment of aggression in children.

TRAAY Guidelines

Outline the optimal treatment strategies for use of antipsychotics in treating aggression in youth.
In aggressive youth with comorbid ADHD they recommend first-line treatment with psychostimulants, followed by psychosocial intervention, and adding a second-generation antipsychotic as a third-line therapy if the combination of a stimulant and a psychosocial intervention is ineffective.

T-MAY Guideline

Recommends starting medication treatment for any underlying condition and adding an antipsychotic if significant aggression persists.
Specifically recommends avoiding the use of more than two psychotropics and mentions the scarcity of long-term data regarding the use of combination therapy in children.
All four recommendations are based largely on expert consensus, but the TRAAY and T-MAP guidelines notably also incorporate evidence-based information.
The similarities of these guidelines demonstrate considerable consistency among experts on the role of combination therapy in the treatment of comorbid ADHD and DBDs.
There is a need for high-quality research using large samples of clinically representative children and long-term follow-up to validate these current guidelines.

Efficacy/Effectiveness of Combination Therapy

Six articles were identified evaluating the use of stimulants with an antipsychotic in pediatric patients with ADHD or an equivalent diagnosis from older versions of the DSM.
Only four of these studies involved patients with ADHD comorbid with DBD or aggression.
Two studies were conducted to examine the use of an antipsychotic for treatment of DBDs, but the design allowed for some analysis of the effect of the combination treatment.
Two of these studies directly evaluated the use of antipsychotics in combination with psychostimulants to treat ADHD comorbid with aggression, although only one was placebo-controlled and blinded.

Armenteros et al. (2007)

The sole randomized, placebo-controlled study evaluated the addition of risperidone (n=12) or a placebo (n=13) to treat aggression in children (ages 7 to 12) who were already receiving psychostimulants.
The sole statistically significant difference was an improvement in the overall CAS-P (100% of risperidone-treated children experienced a \geq30% decrease in CAS-P total versus 77% for the placebo; p<0.05).
There were no statistically significant differences between the placebo and treatment groups in any single subscale or in the overall CAS-T.
The placebo group non-significantly outperformed the risperidone group on the CAS-T total (54% experienced a \geq30% decrease in CAS-T total versus 27% respectively; p>0.05), and the reductions in mean CAS-P scores were comparable for placebo and treatment groups.
The CGI-I and CGI-S scales were used as secondary measures, but neither measurement showed a statistically significant difference between placebo and treatment groups.
Adverse effects were comparable between the two groups, although it is notable that the mean BMI in the placebo group decreased from 19.2 to 17.8 over the 4-week study, whereas the mean BMI for the risperidone group underwent a non-significant increase from 18.6 to 18.8 over the same period.
Results from this study suggest a small difference between the effects of a placebo and the effects of risperidone, but it is important to note that there was a large placebo effect in this trial as both groups responded quite favorably to the adjuvant therapy.
Although the differences in changes in BMI were non-significant, the trend toward increased BMI in the risperidone group is especially notable given the short duration of this study.

Kronenberger et al. (2007)

The addition of a second-generation antipsychotic to stimulant therapy was also evaluated in an open-label trial that examined the use of quetiapine and OROS methylphenidate in patients aged 12 –16.
Patients with comorbid ADHD and aggression with diagnoses of either CD or ODD were started on methylphenidate for 3 weeks. Quetiapine was added for all patients who did not have a significant improvement using methylphenidate ( n=24), and combination therapy was continued for 9 weeks.
There were statistically significant improvements in all of these scales both when comparing baseline to the week 3 score (methylphenidate only) and when comparing week 3 to week 12 (methylphenidate compared to quetiapine/methylphenidate combination therapy), and 42 % of patients had a clinically significant improvement in all rating scales.
Almost all patients (96 %) reported at least one adverse event during the quetiapine phase, but these were largely minor.
Although this study suggests that quetiapine is effective in aggression, there are a number of considerations that limit the conclusions that can be drawn from this information.
The lead- in period with methylphenidate is only 3 weeks, so some of the improvement seen in the last 9 weeks may in fact be due to methylphenidate.
This study did not include placebo controls, and thus there is no mechanism to distinguish the true effect of the adjuvant quetiapine from a placebo effect.

Aman et al. (2004)

Included data from two placebo-controlled trials evaluating the use of risperidone in the treatment of aggression in children (aged 5 – 12) with subaverage IQ.
Patients who were already undergoing psychostimulant treatment (n =73) were allowed to continue with their psychostimulants during both 6-week trials.
Post-hoc analysis showed patients receiving stimulants did not differ from those not receiving stimulants in the reduction in disruptive behavior and hyperactivity produced by risperidone compared to the placebo.
Risperidone also produced similar worsening in metabolic parameters in both the stimulant and no-stimulant cohorts.

Findling et al. (2007)

Conducted an 18-week extension to an open-label study to evaluate quetiapine treatment of conduct disorder in children (aged 6–12).
Nine patients who responded well to quetiapine were continued for 18 weeks, and during this time they were allowed to start psychostimulants if deemed necessary.
Seven of the nine patients started a psychostimulant during this extension.
There were no significant changes in any of the conduct or hyperactivity scores from the quetiapine-only baseline over the 18 weeks.
Conclusions that may be drawn from this study are limited as this study is very small, it was an open-label study, and the stimulant prescription was not controlled in any way.

Gittelman-Klein et al. (1976)

12-week randomized, double-blind, placebo-controlled trial comparing placebo, thioridazine, methylphenidate, and the combination of thioridazine/methylphenidate in treating hyperkinetic children (aged 6–12, n=166).
Based on statistically significant improvements in most of the subscales, all treatments were better than placebo, both the combination treatment and methylphenidate monotherapy were superior to thioridazine treatment, but the combination treatment and methylphenidate monotherapy were not significantly different.
The authors also describe a trend toward combination treatment being superior to methylphenidate monotherapy at 4 weeks, but this trend did not continue at 12 weeks.
The combination treatment produced more side effects in the first 4 weeks but fewer side effects at 12 weeks than either monotherapy.

Weizman et al. (1984)

Performed a 4-week double-blind, placebo-controlled, crossover trial of adjuvant propericiazine to ADHD patients (aged 5–11, n=14).
The addition of the antipsychotic to methylphenidate treatment produced a statistically greater improvement than the addition of placebo to methylphenidate (p<0.05), and the authors did not detect any side effects over the 2-week treatment period.

Summary of Efficacy/Effectiveness

These six studies collectively suggest somewhat mixed conclusions.
It is difficult to perform many comparisons between these studies as the various studies used largely different assessment scales, different medications, and tended to have small sample sizes.
Combination therapy with risperidone is superior to a placebo/psychostimulant combination for hyperactivity and conduct, and quetiapine appears to be beneficial in treating aggression in open-label studies.
Effect of adjuvant second-generation antipsychotics on aggression appears to be of low significance when compared to the large placebo effect in a blinded, randomized trial.
No studies have specifically compared monotherapy with second-generation antipsychotics to combination therapy.

Tolerability of Combination Therapy

Given the limited evidence currently available for the efficacy of combining psychostimulants with antipsychotics in treating ADHD comorbid with DBD, a comprehensive evaluation of potential risks is especially important to any clinical decision.
In addition to the six studies outlined above, our search strategy identified three studies available with evidence regarding adverse effects.

Penzner et al. (2009)

Specifically addressed the adverse effects of psychostimulant and antipsychotic use in young patients (aged 7–19) with significant oppositionality and aggression (n=153).
Compared metabolic parameters, weight, prolactin, and sedation between the patients treated with stimulants and those who were not.
There were no significant differences for the changes in any of these parameters between the two groups and in broad measures of effectiveness there were also no significant differences between groups.

Calarge et al. (2009)

Analyzed detailed metabolic data for 99 patients in a naturalistic study of the metabolic risks associated with risperidone treatment.
Found that psychostimulant use did not significantly alter the weight gain resulting from risperidone treatment after accounting for the baseline adjusted BMI score.

Zeni et al. (2009)

Examined the use of adjuvant methylphenidate to treat ADHD, manic, and depressive symptoms in juvenile (aged 8–17) bipolar patients (n=16) with well-controlled manic symptoms taking aripiprazole.
Both the counts of side effects and the Stimulants Adverse Events Rating Scale (SAERS) did not differ significantly between the methylphenidate and the placebo groups.

Summary of Tolerability

These studies do not suggest significant increases in the frequency of adverse events associated with combination therapy compared to monotherapy with either class of drug.
All described studies are relatively short in duration and have small sample sizes.
Results suggest that stimulant therapy does not provide a significant protective effect against the weight gains and metabolic changes associated with second-generation antipsychotic treatment.

Conclusion

Combination therapy with antipsychotics and psychostimulants is common.
The combination is only suggested as a third-line therapy, following monotherapy and behavioral interventions.
Despite the established efficacy of antipsychotic monotherapy and stimulant monotherapy in DBD and ADHD, the evidence for use in combination is currently limited.
Several studies demonstrated that antipsychotic-induced weight gain is not significantly ameliorated by prescription of psychostimulants.
Benefits are not yet clearly established by randomized controlled trials.
Future research is needed to compare combination therapy to monotherapy with either a stimulant or with an antipsychotic in a placebo-controlled and blinded manner.
Patients undergoing combination therapy should be closely monitored for adverse effects, especially metabolic side effects.