This study suggests that valproate may be effective in the treatment of irritability in ASD. There are several reasons why this may be the case. First, the GABA-enhancing mechanism of valproate may be relevant to both the pathophysiology of aggression and that of ASD (Bjork et al, 2001
; Casanova et al, 2003
). Second, the documented ability of valproate to inhibit kindling has been proposed as an additional mechanism that may explain its effectiveness in treating mood lability, and as such, may be particularly important in the treatment of irritability (Soderpalm, 2002
). Third, the treatment of underlying epileptiform abnormalities may contribute to behavioral response. This theory, although controversial, is supported by our very preliminary data that showed that children randomized to divalproex sodium with epileptiform EEGs were classified as responders. This hypothesis is further supported by a report by Stoll et al (1994)
, who reviewed 115 bipolar and schizoaffective lithium-refractory patients and found that those with a seizure or head injury history and abnormal EEG findings were much more likely to have a robust response to valproate (70%). Of interest, our sample had a mean nonverbal IQ below 70 and a systematic review of the literature has suggested that children with IQs under 70 are more likely to have seizures and epileptiform EEGs (Amiet et al, 2008
). However, the usual pattern did not hold true, with the mean IQ actually being higher in children with epileptiform abnormalities than in children with nonepileptiform EEGs. Thus, our small sample does not support this well-documented phenomenon, but is limited by a small sample size.
We would also like to make note of our preliminary findings suggesting that therapeutic blood levels of valproate are associated with better response. Such results are congruent with data from a large study of valproate in adults with acute mania, in which it was reported that subjects with valproate blood levels of 87
mcg/ml or higher had improvement that was twice the effect size compared with subjects with blood levels less than 87
mcg/ml (Allen et al, 2006
). Although our sample size did not allow for proper dose response and blood level response analysis, it is suggestive enough to highlight the need for a larger study designed and powered to address this issue.
The results of this study are not congruent with the report from the previous small randomized study of this drug in ASD (Hellings et al, 2005
). As previously mentioned, the authors reported high intersubject variability and a large placebo effect, and recommended further evaluation. We would like to suggest that our strategy of stratifying for irritability severity at baseline and enrolling only those subjects with significant difficulties in this domain may be responsible for decreased intersubject variability and increased power in this study.
The safety profile of valproate in this study was very good. One should not assume though that the safety profile of a medication in a short-term study would be reflective of a long-term safety with this medication. Reported side effects of this medication include abdominal discomfort, nausea/vomiting, ataxia and tremor, hyperamonnemic encephalopathy, headaches, and weight gain. Serious side effects such as hepatic insufficiency and agranulocytosis have been rarely reported. One should consider the fact that the frequency of the rare side effects is much higher in children under the age of 2 years, and as such, the use of this medication in that age group remains controversial. There is also much controversy on the prevalence of polycystic ovarian syndrome, which is of concern to parents of high-functioning children in terms of its effects on fertility. Finally, although only one child in our cohort showed significant weight gain, such a side effect has been reported extensively in studies on other disorders, and follow-up studies will be critical in assessing the risk for cardiovascular and metabolic outcomes.
Limitations of our study include the relatively small sample size, which did not allow for a complete analysis of EEG and valproate blood level data. In addition, the absence of an EEG record at the end of the study makes it impossible for investigators to determine whether an improvement in EEG patterns correlated with treatment response. The choice of the ABC-Irritability subscale, although a validated measure in ASD, precludes us from making recommendations regarding specific types of aggression that may be responsive to divalproex. The fact that only seven children had previous exposure to an atypical antipsychotic also did not allow us to explore whether those with previous risperidone treatment were less responsive to valproate vs those without previous risperidone, and this remains a question for a future trial.
Of interest, there was no change in Vineland scores in this acute trial. The effect sizes of improvement noted in Vineland in the RUPP risperidone studies were small to medium and documented mostly at 6 months of treatment (Williams et al, 2006
). In the acute phase and with our sample size, we did not have the power to detect such effects. Qualitative reports of relief due to decreased aggression did not seem to affect the scores on Vineland. There was also no change in CGI-I autism, which is not surprising, given that core symptom domain severity was scored within this measure. Finally, OAS-M did not seem to be sensitive to the changes detected by ABC. OAS-M is not a validated measure in ASD and does not have pediatric psychometric data, and we identified conceptual issues related to how this scale is scored that make it difficult to obtain reliable information in this population. For example, a child with relatively benign repetitive hitting of her chest that was continuous throughout the day was likely to get worse scores than children with more rare but severe self-injury.
Although it is hard to compare the effect size of a pilot study with that of a multicenter trial, the effect size for improvement on the ABC-Irritability subscale is moderate, but less than what was reported in the RUPP risperidone trial (very large). A follow-up of larger trials will be required for an appropriate comparison between the two drugs in terms of effect size of response and safety. In addition, a larger sample study powered to address the question of whether the presence of epileptiform abnormalities, while controlling for IQ, affects differential treatment response to anticonvulsants compared with atypicals, and whether treatment response is mediated by improvements in epileptiform abnormalities is required.