Overall, the finding of few moderators of risperidone response is scientifically disappointing but clinically encouraging, although it should be noted that the possibility of Type II errors (false negatives) can not be ruled out. These results suggest that risperidone is effective for a wide range of children with autism and irritability, aggression, self-injury, and other disruptive behaviors. Only one variable was found to be a significant moderator of response to risperidone: Initial ABC Irritability subscale score. The fact that high initial severity on the ABC Irritability subscale at baseline is related to greater improvement from baseline than low initial severity is intuitively reasonable. The high-severity risperidone group had more room to improve and thus could show more improvement. Regression to the mean cannot account completely for the greater improvement because overall declines were virtually identical for both high and low initial-irritability placebo groups (parallel slopes). Possibly a better explanation could be the behavioral pharmacology phenomenon of rate dependency (Sahakian and Robbins 1977
), in which treatment tends to “normalize” the target symptom regardless of initial severity, similar to aspirin’s reducing any fever to the same normal temperature. Inspection of the graph in confirms that regardless of initial severity, the outcome at 8 weeks is very similar. The practical clinical conclusion, again not revolutionary, is that the risk/benefit ratio of risperidone is more favorable for those with greatest severity.
Due to missing blood specimens, the sample sizes of the blood mineral data were considerably smaller than those for other variables, with consequent loss of power and increased risk of false-negative errors. Therefore the mineral marginal trends, such as ceruloplasmin radial immunodiffusion (RID) moderation (p
= 0.027; see ), are worth exploring in a larger sample, although no conclusions can be drawn from this study.
The nonspecific predictors of outcome () were numerous. Most were variables that predicted poorer response, regardless of the treatment to which the child was randomized. It seems intuitive that a child with various psychological and behavioral symptoms beyond those required for study entry, like those on CSI and ABC subscales referenced in , would experience poorer outcome than a child without such a burden. Parent income and education were positively associated with outcome, which is consistent with more family resources being available to help the child. Inspection of the raw data in suggests that the general prediction of response by baseline prolactin level may have actually been a moderator that lacked sufficient power to show statistical significance (the significance level of the three-way interaction was 0.053, a possible false negative). Lower baseline prolactin predicted more improvement (reduction by 19.1. vs. 12.5) in the risperidone group, but not in the placebo group, which actually showed a nominal tendency the other direction (4.32 vs. 4.85). Low baseline prolactin predicted better outcome only in the risperidone group, and this effect was strong enough to carry the whole sample with a significance level (0.000) that would withstand severe correction for multiple tests. Thus, the association of lower baseline prolactin with better outcome could be compatible with a hypothesis that those with lower prolactin might benefit more from, or be able to tolerate higher doses of, a drug that raises prolactin. However, in this sample, baseline prolactin and risperidone dose did not correlate, casting doubt on the latter (tolerability) hypothesis. The hypothesis of greater benefit from the same dose when starting with low prolactin would be partially supported by correlation of improvement with prolactin increase, but the modest tendency in this direction was not significant.
Weight gain was the only significant mediator of response to risperidone. It is well known that risperidone and other antipsychotics are commonly associated with weight gain (Allison et al. 1999
), and, in this sample, active medication and weight gain were significantly correlated. The mediating effect of weight gain, however, was a negative one for risperidone. In another analysis including the placebo nonresponders from this study who received an open trial of risperidone as well as those originally assigned to risperidone (total n
72 receiving risperidone), McCracken et al. (2009) found that weight gain (in kg) was significantly negatively correlated with improvement in ABC Irritability subscale score (r
0.048). We cannot infer that weight gain worsened outcome, because in the placebo group it was positively associated with improvement. One might suspect that the finding could be an artifact of those with less favorable clinical outcomes having their dose pushed higher than those with more favorable outcomes; if side effects, including weight gain, increased with dose, this could cause an association of poorer outcome with weight gain. However, this explanation would not be compatible with the dose analysis, in which those taking higher doses of risperidone had at least as good outcomes as those taking lower doses (). In any event, the finding does suggest that amending risperidone treatment in some way to prevent weight gain should not interfere with clinical benefit and might even increase the effectiveness. One way to explore this might be a randomized controlled trial of risperidone alone versus risperidone plus diet and exercise or versus risperidone plus metformin to prevent weight gain. Metformin, an antidiabetic drug, has been reported to be safe and effective to combat weight gain of antipsychotics in adults (Wu et al. 2008
) and children (Klein et al. 2006
). If the treatment including weight gain prevention produced better symptom outcomes than risperidone alone, then weight gain would be a negative mediator of some clinical value, and the behavioral effect would add to the physical health value of preventing excessive weight gain.
The association of dose with outcome may have been an artifact of the study titration combined with the method with which we analyzed the data (following Kraemer et al. 2002
). Both treatment groups were included in the analysis. In this study, dose was titrated against clinical effect and side effects in both treatment groups. It is not unexpected that higher doses were associated with worse outcome for the placebo group relative to lower doses, while dose did not significantly affect response to risperidone, which was titrated to an individually optimal dose. These findings are consistent with a physician prescribing increasing levels of placebo in the face of unimproved behavior and no side effects. Indeed, the mean and median doses were higher for placebo than for risperidone (2.4 and 1.7
mg vs, 1.7 and 1.3
mg, respectively). Although interesting, this finding is probably not clinically relevant to treatment with risperidone other than suggesting that it is possible to titrate individually to a consistent level of symptom control.
Compliance was related to outcome as predicted. Overall, compliance levels were high, a result of relatively tight monitoring. Within the risperidone group, good compliance was associated with better outcome than was noncompliance, but this association did not hold for the placebo group. Ostensibly, those participants who were able to comply better with dosing were able to reap the benefits of risperidone treatment. Of course, one might argue that they were able to comply because they were already better, but this argument would be incompatible with not finding such an effect in the placebo group. It is interesting that the regression lines shown in predict that at a compliance level of about 90%, the response to risperidone would essentially equal the average placebo response. This finding reinforces the common knowledge that compliance is important.
The enzyme 5′-nucleotidase requires zinc for activity, so it has been studied for indication of zinc status in people without liver problems (which could elevate its levels) (Bales et al. 1994
; Prasad 1994
; Blostein-Fujii et al. 1997
). Although the relationship of zinc status to 5′-nucleotidase activities in growing children has not been directly studied, it has been studied in other contexts. Plasma or serum 5′-nucleotidase activities have reflected moderate changes in zinc status in diabetic adult women (Blostein-Fujii et al. 1997
), in elderly men and women (Bales et al. 1994
), in young adult women (Zhang W, DiSilvestro RA, unpublished results), and in growing rats (DiSilvestro RA, unpublished results). Results have to be interpreted in the light of children tending to have lower 5′-nucleotidase serum activities than adults (Belfield and Goldberg 1971
). In this sample, serum 5′-nucleotidase change was itself moderated by risperidone; if a child experienced a decrease in serum 5′-nucleotidase while taking risperidone (but not placebo), then (s)he was likely to experience greater improvement in irritability than those with 5′-nucleotidase increase. This suggests that increases in body zinc status are associated with less improvement with risperidone. However, this suggestive association is qualified by the absence of a parallel relationship between plasma zinc level and ABC Irritability subscale score improvement. Nevertheless, the finding was of such high significance (p
0.0001) that it would withstand severe correction for multiple testing and deserves exploration in future studies.
This study has several limitations, including missing data for the mineral assays, which depended on frozen leftover serum from other blood tests. There is risk of both Type I error from multiple tests and Type II error from insufficient power from subdividing the sample. One might argue that the alpha of 0.01 was not adequate correction for multiple tests, but we felt it struck a reasonable balance between the two error possibilities in these exploratory analyses. As it happened, most of the significant findings had p values that would have withstood several-fold greater Bonferroni correction, so this may be a moot point. The marginal trends at 0.01< p < 0.05 (e.g., ceruloplasmin moderation and ferritin mediation) could conceivably be false negatives, but could also just be chance variations. The only way to tell is to repeat the analyses in a new (and larger) sample.