A Positive Placebo-Controlled Trial of Valproate (Depakote) in Autism
A recent issue of the Journal of Neuropsychopharmacology reported that a placebo-controlled trial of valproate (Depakote) showed the drug is effective in treating irritability in those with autism. Approximately 50% of the participants were less irritable on valproate compared with only about 15% on placebo. Valproate was also generally well-tolerated.
EDITOR’S NOTE: This is a particularly important finding, both for clinical treatment and for its potential theoretical implications. Valproate, in addition to its properties as a mood-stabilizing anticonvulsant that increases brain GABA levels and exerts a variety of other neurobiological effects, is also a histone deacetylase inhibitor.
Histone deacetylase inhibitors may counteract problems with excitatory transmission. There is increasing evidence that in several animal models of autism and in patients with genetic disorder fragile X, there is increased binding of protein MeCP2 to DNA, which inhibits excitatory transmission. The main excitatory neurotransmitter in the CNS is glutamate, which is intimately involved in neuronal development, synaptic plasticity, and learning and memory. Thus a lower amount of excitatory neurotransmission could have profound effects on development in the short and long terms. In one animal model, the inhibitory effect of MeCP2 was reversed by treating the animals with two deacetylase-inhibiting drugs in combination that together blocked both histone-deacetylase type 3 and type 4. The deacetylase inhibitors keep acetyl groups on histones and render DNA more likely to be transcribed (or turned on).
Valproate exerts clinically significant histone-deacetylase activity on both type 3 and type 4 enzymes, which may explain its efficacy in autistic spectrum disorders. To clarify whether this is the mechanism by which valproate works, future studies could compare valproate with other drugs such as valnoctamide, which is an equally effective antimanic drug, but does not inhibit histone-deacetylase. Should valproate alone prove effective in the treatment of autism, it would be likely that valproate’s therapeutic effects depend on its histone-deacetylase mechanism.
As previously discussed in BNN Vol. 13(1), 2009, environmental factors can affect how easily DNA is transcribed by altering both DNA methylation and histone acetylation or methylation. Environmental events dictate the amount of methylation and acetylation, which is why the process is described as epigenetic. The inherited DNA code is not altered, only the degree to which additional molecules get attached to it during an animal’s lifetime. DNA is tightly wrapped around histones, and when histones are acetylated, DNA is in a more open conformation, making it easier to transcribe.
Transcription basically consists of a read-out of the DNA and the construction of a chain of messenger RNA (mRNA), which then travels to the protein synthesis machinery of the cell (endoplasmic reticulum) in order to dictate the synthesis of new proteins based on the specific RNA sequences that code for individual amino acids. This production of new proteins by sequentially attaching strings of amino acids together based on the mRNA code is called translation.
In autism there appears to be a deficit in DNA transcription and subsequent mRNA translation of proteins in the brain that are important for ensuring adequate amounts of excitatory neurotransmission in the glutamate system. Thus, there is great potential for alleviating some symptoms of autism by preventing the removal of acetyl groups by de-acetylases in order to maintain higher levels of histone acetylation. With a histone-deacetylase inhibitor such as valproate, more histones remain acetylated and thus DNA is more readily transcribed. This could reverse the effects of MeCP2 in inhibiting excitatory neurotransmission in models of autism and in the fragile x syndrome.
If the valproate efficacy data are replicated and are ultimately attributed to inhibition of histone-deacetylation, this would open a whole new arena of potential therapeutic approaches to this most disabling disorder.
An environmentally-mediated epigenetic mechanism might also be consistent with the remarkable increased incidence of autism in more recent years. Autism was a relatively rare condition some two or three decades ago, but now is recognized in 1 per 100 to 125 live births. Currently only the atypical antipsychotics Aripiprazole (Abilify) and risperidone (Risperidol) are FDA-approved for the treatment of irritability in autism.
Comments
Leave a Reply
