Glutamate Transmission Enhancement for Treatment of PTSD

摘要

Although now considered to be the most effective treatment for post traumatic stress disorder (PTSD), extinction based therapies require substantial time and investment for both the patient and provider, averaging 10 sessions or more of approximately 1h each to achieve significant beneficial effects. Thus, treatments that enhance the efficacy of extinction therapies and reduce the number of required sessions for remission would be of great benefit. Ideally, such adjunctive treatments may reduce the need for long term medication. Preclinical studies have demonstrated that glutamate transmission in the amygdala is necessary for long term extinction of fear memories. Furthermore, d-cycloserine (DCS), a partial NMDA receptor agonist acting on the glycine modulator site, significantly enhances fear extinction (fear extinction). DCS treatment has also been shown to significantly enhance efficacy of extinction-based therapy across a number of anxiety disorders. However, efficacy of DCS may be limited, as its effects diminish over repeated dosing and it is not effective in all subjects or protocols. Here we will examine the efficacy of 2 novel classes of compounds which enhance glutamate signal to facilitate fear extinction. First, we will examine the efficacy of Org-24598, a glycine transporter 1 (GLYT1) inhibitor to increase fear extinction. GLYT1 inhibition has been shown to facilitate glutamate transmission in limbic regions that modulate emotional processes, and are more efficacious in facilitating glutamate signal than DCS. Second we will examine the efficacy of CX546, a positive allosteric modulator of AMPA receptors to increase fear extinction.