Image by Holger Langmaier from Pixabay

February 20th, 2023

Some people may have seen the new press regarding autism. In a new study from Nature Molecular Psychiatry, we have some more data looking at the use of Lamotrigine, an anticonvulsant medicine, in the treatment of autism spectrum disorder. This could be exciting new news. Key word could.

Moritz Mall, lead scientist, noted that the MYT1L protein is associated with ASD type neuronal symptoms. The MYT1L protein is a transcription factor that helps determine which genes in a cell are turned on or off. This protein helps cells maintain a differentiated path to become a nerve cell.

Several neurological diseases, such as schizophrenia and epilepsy, as well as brain malformations, have been linked to MYT1L mutations.

His group genetically silenced the MYT1L genes in mice and human stem cells in a lab. The net effect was electrical hyper activation leading to poor neuronal function. The gene altered mice exhibit neurodevelopmental delays with thinner brain cortical volume; behavioural symptoms and gene expression changes that resemble those of ASD patients. The etiology was due to an up regulation of sodium channels leading to aberrant electrical conduction. This effect was blunted by the antagonist drug Lamotrigine.

The important piece of this study was the clinical fact that the ASD symptoms were beneficially affected by the drug.

This bears some solid double blind placebo study to prove causation and disease amelioration. Exciting mechanistic data!

When I searched for current studies clinically, I could only find one to date with lamotrigine. The findings were not beneficial in 28 study children published in 2001. A meta analysis of 7 studies with three different anticonvulsants showed no benefit either. See below for details.

We keep searching.



"MYT1L is an autism spectrum disorder (ASD)-associated transcription factor that is expressed in virtually all neurons throughout life. How MYT1L mutations cause neurological phenotypes and whether they can be targeted remains enigmatic. Here, we examine the effects of MYT1L deficiency in human neurons and mice. Mutant mice exhibit neurodevelopmental delays with thinner cortices, behavioural phenotypes, and gene expression changes that resemble those of ASD patients. MYT1L target genes, including WNT and NOTCH, are activated upon MYT1L depletion and their chemical inhibition can rescue delayed neurogenesis in vitro. MYT1L deficiency also causes upregulation of the main cardiac sodium channel, SCN5A, and neuronal hyperactivity, which could be restored by shRNA-mediated knockdown of SCN5A or MYT1L overexpression in postmitotic neurons. Acute application of the sodium channel blocker, lamotrigine, also rescued electrophysiological defects in vitro and behaviour phenotypes in vivo. Hence, MYT1Lmutation causes both developmental and postmitotic neurological defects. However, acute intervention can normalise resulting electrophysiological and behavioural phenotypes in adulthood. " (Weigel et. al. 2023)

"In autism, glutamate may be increased or its receptors up-regulated as part of an excitotoxic process that damages neural networks and subsequently contributes to behavioral and cognitive deficits seen in the disorder. This was a double-blind, placebo-controlled, parallel group study of lamotrigine, an agent that modulates glutamate release. Twenty-eight children (27 boys) ages 3 to 11 years (M = 5.8) with a primary diagnosis of autistic disorder received either placebo or lamotrigine twice daily. In children on lamotrigine, the drug was titrated upward over 8 weeks to reach a mean maintenance dose of 5.0 mg/kg per day. This dose was then maintained for 4 weeks. Following maintenance evaluations, the drug was tapered down over 2 weeks. The trial ended with a 4-week drug-free period. Outcome measures included improvements in severity and behavioral features of autistic disorder (stereotypies, lethargy, irritability, hyperactivity, emotional reciprocity, sharing pleasures) and improvements in language and communication, socialization, and daily living skills noted after 12 weeks (the end of a 4-week maintenance phase). We did not find any significant differences in improvements between lamotrigine or placebo groups on the Autism Behavior Checklist, the Aberrant Behavior Checklist, the Vineland Adaptive Behavior scales, the PL-ADOS, or the CARS. Parent rating scales showed marked improvements, presumably due to expectations of benefits." (Belsito et. al. 2001)

"Electroencephalogram-recorded epileptiform activity is common in children with autism spectrum disorder (ASD), even without clinical seizures. A systematic literature search identified 7 randomized, placebo-controlled trials of antiepileptic drugs (AEDs) in ASD (total n = 171), including three of valproate, and one each of lamotrigine, levetiracetam, and topiramate. Meta-analysis revealed no significant difference between medication and placebo in four studies targeting irritability/agitation and three studies investigating global improvement, although limitations include lack of power and different medications with diverse actions. Across all seven studies, there was no significant difference in discontinuation rate between two groups. AEDs do not appear to have a large effect size to treat behavioral symptoms in ASD, but further research is needed, particularly in the subgroup of patients with epileptiform abnormalities." (Hirota et. al. 2014)

Nature Molecular Psychiatry
Belsito J Autism and Develop Disorders
Hirota J Autism and Develop Disorders







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