part three: the questions…

Posted on Monday 7 July 2014

As for efficacy, Tyrer et al say [see part one: the bind…]:
    What is the evidence for the benefits of these drugs in the treatment of challenging behaviour? Virtually none. Almost all the evidence in favour comes from small trials conducted by drug companies. Yet it would be perverse if doctors continued to prescribe these drugs, knowing about their adverse effects, if they were entirely without efficacy, and many claim that they cannot care adequately for their patients without the option of drug treatment…
In 2012, a Cochrane Systematic Review [not limited to children with mental retardation] found only eight studies of a quality to include – seven with Risperdal® and one with Seroquel®:
by Loy JH, Merry SN, Hetrick SE, and Stasiak K.
Cochrane Database of Systematic Reviews. 2012 9:CD008559 .

BACKGROUND: Disruptive behaviour disorders include conduct disorder, oppositional defiant disorder and disruptive behaviour not otherwise specified. Attention deficit hyperactivity disorder [ADHD] is frequently associated with disruptive behaviour disorders. The difficulties associated with disruptive behaviour disorders are demonstrated through aggression and severe behavioural problems. These often result in presentation to psychiatric services and may be treated with medications such as atypical antipsychotics. There is increasing evidence of a significant rise in the use of atypical antipsychotics for treating disruptive behaviour disorders in child and adolescent populations.
OBJECTIVES: To evaluate the effect and safety of atypical antipsychotics, compared to placebo, for treating disruptive behaviour disorders in children and youths.
SEARCH METHODS: We searched the following databases in August 2011: CENTRAL… MEDLINE… EMBASE… PsycINFO… CINAHL…… Australian New Zealand Clinical Trials Registry… CenterWatch… and ICTRP…
SELECTION CRITERIA: We included randomised controlled trials with children and youths up to and including the age of 18, in any setting, with a diagnosis of a disruptive behaviour disorder. We included trials where participants had a comorbid diagnosis of attention deficit hyperactivity disorder, major depression or an anxiety disorder…
MAIN RESULTS: We included eight randomised controlled trials, spanning 2000 to 2008. Seven assessed risperidone and one assessed quetiapine. Three of the studies were multicentre. Seven trials assessed acute efficacy and one assessed time to symptom recurrence over a six-month maintenance period.We performed meta-analyses for the primary outcomes of aggression, conduct problems and weight changes but these were limited by the available data as different trials reported either mean change scores [average difference] or final/post-intervention raw scores and used different outcome measures. We also evaluated each individual trial’s treatment effect size where possible, using Hedges’ g.For aggression, we conducted two meta-analyses. The first included three trials [combined n = 238] using mean difference [MD] on the Aberrant Behaviour Checklist [ABC] Irritability subscale. Results yielded a final mean score with treatment that was 6.49 points lower than the post-intervention mean score with placebo [95% confidence interval [CI] -8.79 to -4.19]. The second meta-analysis on aggression included two trials [combined n = 57] that employed two different outcome measures [Overt Aggression Scale [modified] [OAS-M] and OAS, respectively] and thus we used a standardised mean difference. Results yielded an effect estimate of -0.18 [95% CI -0.70 to 0.34], which was statistically non-significant.We also performed two meta-analyses for conduct problems. The first included two trials [combined n = 225], both of which employed the Nisonger Child Behaviour Rating Form – Conduct Problem subscale [NCBRF-CP]. The results yielded a final mean score with treatment that was 8.61 points lower than that with placebo [95% CI -11.49 to -5.74]. The second meta-analysis on conduct problems included two trials [combined n = 36], which used the Conners’ Parent Rating Scale – Conduct Problem subscale [CPRS-CP]. Results yielded a mean score with treatment of 12.67 lower than with placebo [95% CI -37.45 to 12.11], which was a statistically non-significant result.With respect to the side effect of weight gain, a meta-analysis of two studies [combined n = 138] showed that participants on risperidone gained on average 2.37 kilograms more than those in the placebo group over the treatment period [MD 2.37; 95% CI 0.26 to 4.49].For individual trials, there was a range of effect sizes [ranging from small to large] for risperidone reducing aggression and conduct problems. The precision of the estimate of the effect size varied between trials.
AUTHORS’ CONCLUSIONS: There is some limited evidence of efficacy of risperidone reducing aggression and conduct problems in children aged 5 to 18 with disruptive behaviour disorders in the short term. For aggression, the difference in scores of 6.49 points on the ABC Irritability subscale [range 0 to 45] may be clinically significant. 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. Caution is required due to the limitations of the evidence and the small number of relevant high-quality studies. The findings from the one study assessing impact in the longer term suggest that the effects are maintained to some extent [small effect size] for up to six months. Inadequately powered studies produced non-significant results. The evidence is restricted by heterogeneity of the population [including below average and borderline IQ], and methodological issues in some studies, such as use of enriched designs and risk of selection bias… Further high-quality research is required with large samples of clinically representative youths and long-term follow-up to replicate current findings.
Nothing much to write home about there – confirming Tyrer et al’s point that although the use of antipsychotics in intellectually impaired kids with challenging/disruptive behavior is near "Dogma," it’s not "evidence-based Dogma." It’s just what "doctors-habitually-think-Dogma." So all the questions remain unanswered:
  • Are [Atypical] Antipsychotics effective in managing challenging/disruptive behavior in intellectually impaired children? or for that matter, children with other non-psychotic diagnoses? Short term? Long term?
  • What is the incidence of various Adverse Effects using [Atypical] Antipsychotics in intellectually impaired children? or again, children with other non-psychotic diagnoses? Short term? Long term? Are these drugs actually harmful?
  • What are alternative recommendations for managing challenging/disruptive behavior in retarded children? or children with other non-psychotic diagnoses? Short term? Long term?
The ubiquitous influence of the pharmaceutical industry and the cost-cutting restrictions of managed care have had an enormous influence on the way we approach issues like this over the last fifty years. The editorial by Tyrer points out that the use of antipsychotics [I would add particularly Atypical Antipsychotics, particularly Risperdal®] is based on a belief that has achieved the level of Dogma, but the basis for that belief is hardly confirmed by the available scientific record. The problem their editorial addresses – the use of antipsychotics in mentally retarded children – seems to me to encompass an even greater domain than they mention i.e. Autism, primary behavioral problems, whatever-the-Biederman-Bipolar-kids represented, other non-psychotic conditions. And the answer to the question "What is the best practice response, if any, to challenging/disruptive behavior in children with intellectual impairment?" is actually unknown, as is specifically "What is the place of antipsychotics, if any?"

Parenthetically, I marvel at how a study like Aman et al’s [Risperidone Disruptive Behavior Study Group] Double-Blind, Placebo-Controlled Study of Risperidone for the Treatment of Disruptive Behaviors in Children With Subaverage Intelligence can have such a large effect over the years. It was a small industry run study that was part of a failed attempt early on get approval for the behavioral management of mentally retarded children. It was reincarnated as a justification for using antipsychotics in kids with "super angry/grouchy/cranky irritability" that came to be called Bipolar, at least for a time. And here fifteen years later, it remains as 1/7th of the literature suitable for the Cochrane meta-analysis.

I’m aware that I put more emphasis on the impact of PHARMA on this prescribing practice than Tyrer et al. I don’t think that’s because I’m some kind of wild-eyed activist. I think it’s because I heard it in person with my own ears when I went to the J&J/TMAP trial in Austin in January 2012 [State of Texas and Allen Jones v. Janssen et al]. If you find yourself doubting that influence, I’ve posted the transcripts of that trial. I would recommend reading the testimony of sales rep Tiffany Moake and particularly sales manager Tone Jones [here and here]. I can pretty much guarantee that you will come around to my view before you are halfway through.
    Steve Lucas
    July 7, 2014 | 1:40 PM

    While this link reflects a different class of drugs I think the similarities are interesting:

    The push on the part of pharma to sell drugs with no or little scientific study is common.

    Steve Lucas

    Nancy Wilson
    July 8, 2014 | 7:58 PM

    You are in good company, Mickey. Look here:

    Drug Abuse: Antipsychotics in Nursing Homes by Jan Goodwin, AARP Bulletin, July/ August 2014

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