**6. Conclusion**

308 Pharmacology

Some NMDA antagonists appear to be neuromodulators that reduce the excitotoxicity effects of dysregulated circuits and support dendritic health, long term potentiation and neural plasticity. Such treatments may one day provide preventative pharmacological

Two NMDA antagonists are particuilarly interesting candidates for therapeutic potential in the ASD population, memantine and dextromethorphan/quinidine (Duke & Kaye,

Memantine, as an augmenting agent, demonstrated significant improvements in open-label use for language function, social behavior, and self-stimulatory behaviors, although selfstimulatory behaviors comparatively improved to a lesser degree. Chronic use so far

Dextromethorphan/quinidine (DM/Q) shares the attributes of being an uncompetitive NMDA antagonist with memantine, however, importantly; DM/Q is a sigma 1 agonist and binds to SERT. Binding data comparing memantine with DM/Q demonstrate the presence

One of the characteristics that suggests DM/Q might have therapeutic potential in ASD is its efficacy in pseudobulbar affect (PBA). The efficacy and safety of dextromethorphan and quinidine was demonstrated in clinical trials of late stage neurological conditions (amyotrophic lateral Sclerosis and Multiple Sclerosis) demonstrating reductions of emotional lability and improvements in sleep. These findings suggest that the pharmacological characteristics of DM/Q may, at some level rescue synaptic signaling and may have the potential to affect neurodevelopmental trajectory in dysregulated developing

AVP-923 was approved by the FDA in 2010 as Nuedexta™ the first and only treatment for Pseudobulbar Affect (PBA). This is an important therapeutic for those suffering the debilitating effects of pseudobulbar affect. The efficacy in reducing dysregulated and involuntary congruent and incongruent emotional expressions is a significant achievement. Why is DM/Q (Nuedexta) effective in PBA? That, of course, is unknown, but PBA is often considered the result of connectivity and neural circuitry failures and ASD is known to have signaling and connectivity pathologies. Emotional lability is often associated with behavioral dyscontrol, irritibility, assaultive and raging behaviors that prompt

NMDA antagonists may offer a therapeutic pathway through modulation or regulation of dysregulated glutamatergic processes. The potential of DM/Q (Nuedexta) in ASD, particularly in the early developmental stages of the illness, to rescue and support synaptic

Although the mechanism of action of DM/Q is not fully characterized, its unique properties as an NMDA receptor antagonist and as a Sigma 1 receptor agonist appear to convey effects of both neuroprotection and neuromodulation. Future studies will help us determine if these unique characteristics will lead to improved outcomes for those with autism spectrum

of Sigma 1 and SERT binding in DM/Q but not in memantine (Werling, et al 2007).

interventions as well as those that can reduce impairment and improve functioning.

appears to have no serious side effects (Chez MG, et al 2007).

nervous systems such as those with Autism Spectrum Disorders.

pharmacological intervention in children with ASD.

function is worthy of further study.

disorders.

2010).

The distress, irritability and emotional lability often seen in Autism Spectrum Disorders may be a reflection of pathological glutamatergic functioning or otherwise dysregulated circuits relative to inhibitory-excitatory balance. When sustained, these symptoms demonstrate potential for pathological development of abnormal neural circuits capable of dysregulation through neural synchronicity and state dependent effects on genetic expression. Within the framework of this hypothesis the neural plasticity and critical periods, present in developing brains, place them at particular risk.

We currently have drugs and compounds that have the ability to reduce impairment and improve functioning in many with ASD when used, monitored and managed thoughtfully. Early pharmacological intervention related to severe emotional lability, irritability and dysregulated circuits may also reduce the pathogenic potential and reduce or prevent the development or maintenance of pathological processes.
