Atypical antipsychotic drugs for disruptive behaviour disorders in children and youths

Review question

To review the effect and safety of atypical antipsychotics (which are newer-generation major tranquillisers), compared to placebo (dummy pill), for treating disruptive behaviour disorders (e.g. defiance, disobedience, hostility) in children and youths.

Background

Children and youths with disruptive behaviour disorders often present with aggression and severe behaviour problems. These can result in families seeking health services, where atypical antipsychotics may be used to reduce these symptoms. There is increasing usage of atypical antipsychotics in the treatment of disruptive behaviour disorders.

Study characteristics

We reviewed the evidence for atypical antipsychotics, compared to placebo, for treating disruptive behaviour disorders in children and youths. The evidence is current to 19 January 2017. We found 10 studies. Of these studies, eight investigated the effect of risperidone, one investigated quetiapine and one investigated ziprasidone. Five studies were pilot studies (a small, preliminary study to assess the feasibility, including costs, of conducting a larger study). Five studies had 38 or fewer participants; one study had 50 participants, two studies had over 100 participants each, one had 168 participants and one had over 300 participants. Nine studies had a duration of four, six or 10 weeks. The tenth study was a six-month maintenance trial. Nine out of 10 studies had some degree of pharmaceutical support/funding.

Key results and quality of evidence

Our analysis suggested that risperidone led to a reduction of aggression (low-quality evidence) and conduct problems (moderate-quality evidence), to some extent, after six weeks of treatment, and that risperidone appeared relatively safe in the short-term. However, it was associated with significant weight gain (low- to moderate-quality evidence). There are other side effects that have not been well studied and long-term effects are not entirely clear. Clinicians prescribing such medication and families need to carefully consider the benefits and risks of medications. There were no studies with children under five years of age. There is a lack of studies of medications other than risperidone.

We recommend that more research be conducted to find out the long-term effects and safety of these medications. More research is also needed for other medications besides risperidone. Ideally, medication should be used with or preceded by effective psychosocial treatments, like parent training, consistent with current clinical guidelines. It is important that medications are used at adequate doses and for an adequate duration. Careful thought needs to be given to usage of medications sequentially or in combination in order to optimise the therapeutic effect while minimising polypharmacy.

The findings need to be considered with caution because of the limitations of the evidence. The studies used different outcome measures, which limited our ability to combine the findings. Six out of 10 studies had small numbers of participants, which affected the power of the studies (the ability of the study to distinguish an effect of a certain size from chance). The quality of the evidence for the main outcomes of this review — aggression, conduct problems and weight gain — ranged from low to moderate quality using the GRADE considerations.

Authors' conclusions: 

There is some evidence that in the short term risperidone may reduce aggression and conduct problems in children and youths with disruptive behaviour disorders There is also evidence that this intervention is associated with significant weight gain.

For aggression, the difference in scores of 6.49 points on the ABC ‒ Irritability subscale (range 0 to 45) may be clinically significant. It is challenging to interpret the clinical significance of the differential findings on two different ABS subscales as it may be difficult to distinguish between reactive and proactive aggression in clinical practice. For conduct problems, the difference in scores of 8.61 points on the NCBRF-CP (range 0 to 48) is likely to be clinically significant. Weight gain remains a concern.

Caution is required in interpreting the results due to the limitations of current evidence and the small number of high-quality trials. There is a lack of evidence to support the use of quetiapine, ziprasidone or any other atypical antipsychotic for disruptive behaviour disorders in children and youths and no evidence for children under five years of age. It is uncertain to what degree the efficacy found in clinical trials will translate into real-life clinical practice. Given the effectiveness of parent-training interventions in the management of these disorders, and the somewhat equivocal evidence on the efficacy of medication, it is important not to use medication alone. This is consistent with current clinical guidelines.

Read the full abstract...
Background: 

This is an update of the original Cochrane Review, last published in 2012 (Loy 2012). Children and youths with disruptive behaviour disorders may present to health services, where they may be treated with atypical antipsychotics. There is increasing usage of atypical antipsychotics in the treatment of disruptive behaviour disorders.

Objectives: 

To evaluate the effect and safety of atypical antipsychotics, compared to placebo, for treating disruptive behaviour disorders in children and youths. The aim was to evaluate each drug separately rather than the class effect, on the grounds that each atypical antipsychotic has different pharmacologic binding profile (Stahl 2013) and that this is clinically more useful.

Search strategy: 

In January 2017, we searched CENTRAL, MEDLINE, Embase, five other databases and two trials registers.

Selection criteria: 

Randomised controlled trials of atypical antipsychotics versus placebo in children and youths aged up to and including 18 years, with a diagnosis of disruptive behaviour disorders, including comorbid ADHD. The primary outcomes were aggression, conduct problems and adverse events (i.e. weight gain/changes and metabolic parameters). The secondary outcomes were general functioning, noncompliance, other adverse events, social functioning, family functioning, parent satisfaction and school functioning.

Data collection and analysis: 

We used standard methodological procedures expected by Cochrane. Two review authors (JL and KS) independently collected, evaluated and extracted data. We used the GRADE approach to assess the quality of the evidence. We performed meta-analyses for each of our primary outcomes, except for metabolic parameters, due to inadequate outcome data.

Main results: 

We included 10 trials (spanning 2000 to 2014), involving a total of 896 children and youths aged five to 18 years. Bar two trials, all came from an outpatient setting. Eight trials assessed risperidone, one assessed quetiapine and one assessed ziprasidone. Nine trials assessed acute efficacy (over four to 10 weeks); one of which combined treatment with stimulant medication and parent training. One trial was a six-month maintenance trial assessing symptom recurrence.

The quality of the evidence ranged from low to moderate. Nine studies had some degree of pharmaceutical support/funding.

Primary outcomes

Using the mean difference (MD), we combined data from three studies (238 participants) in a meta-analysis of aggression, as assessed using the Aberrant Behaviour Checklist (ABC) ‒ Irritability subscale. We found that youths treated with risperidone show reduced aggression compared to youths treated with placebo (MD −6.49, 95% confidence interval (CI) −8.79 to −4.19; low-quality evidence). Using the standardised mean difference (SMD), we pooled data from two risperidone trials (190 participants), which used different scales: the Overt Aggression Scale ‒ Modified (OAS-M) Scale and the Antisocial Behaviour Scale (ABS); as the ABS had two subscales that could not be combined (reactive and proactive aggression), we performed two separate analyses. When we combined the ABS Reactive subscale and the OAS-M, the SMD was −1.30 in favour of risperidone (95% CI −2.21 to −0.40, moderate-quality evidence). When we combined the ABS Proactive subscale and OAS-M, the SMD was −1.12 (95% CI −2.30 to 0.06, moderate-quality evidence), suggesting uncertainty about the estimate of effect, as the confidence intervals overlapped the null value. In summary, there was some evidence that aggression could be reduced by risperidone. Data were lacking on other atypical antipsychotics, like quetiapine and ziprasidone, with regard to their effects on aggression.

We pooled data from two risperidone trials (225 participants) in a meta-analysis of conduct problems, as assessed using the Nisonger Child Behaviour Rating Form ‒ Conduct Problem subscale (NCBRF-CP). This yielded a final mean score that was 8.61 points lower in the risperidone group compared to the placebo group (95% CI −11.49 to −5.74; moderate-quality evidence).

We investigated the effect on weight by performing two meta-analyses. We wanted to distinguish between the effects of antipsychotic medication only and the combined effect with stimulants, since the latter can have a counteracting effect on weight gain due to appetite suppression. Pooling two trials with risperidone only (138 participants), we found that participants on risperidone gained 2.37 kilograms (kg) more (95% CI 0.26 to 4.49; moderate-quality evidence) than those on placebo. When we added a trial where all participants received a combination of risperidone and stimulants, we found that those on the combined treatment gained 2.14 kg more (95% CI 1.04 to 3.23; 3 studies; 305 participants; low-quality evidence) than those on placebo.

Secondary outcomes

Out of the 10 included trials, three examined general functioning, social functioning and parent satisfaction. No trials examined family or school functioning. Data on non-compliance/attrition rate and other adverse events were available from all 10 trials.

Share/Save