The Role of the Glutamate System in Posttraumatic Stress Disorder and Glutamate-Based Treatments

Posttraumatic Stress Disorder (PTSD) is a chronic mental illness with limited options for treatment, characterized by intrusive memory of trauma, avoidance, hyperarousal, emotional numbing, and anhedonia. PTSD is often triggered by exposure to a single traumatic experience, with high prevalence among war veterans. PTSD, together with other neuropsychiatric disorders, involves long-term changes in the structure and function of brain areas, synaptic disconnection, and changes in large-scale brain networks. Trauma-focused psychotherapy is considered first-line treatment, with greater and more persistent efficacy than pharmacotherapeutic approaches. Pharmacological treatments include SSRI, particularly paroxetine and sertraline, and other traditional antidepressants. The effect size of efficacy for these drugs is often small, with high treatment resistance in certain populations. In recent years a major shift in the conceptual framework of neuropsychiatric disorders has occurred, from the monoamine hypothesis to a neuroplasticity hypothesis, in which the glutamate system is conceived as a primary mediator of pathology and a straight target for antidepressant drugs. Novel potential treatment options have emerged in recent years, in particular several modulators of the glutamate system, including ketamine, riluzole, d-cycloserine, N-acetylcysteine. Ketamine, the prototypical rapid-acting antidepressant, has received much attention for its complex mechanism of action (including clinical trials), and has been proposed as a prophylactic agent against the onset of PTSD after exposure to traumatic stress. This chapter will explore new pharmacological approaches to the therapy of PTSD, based on the modulation of the glutamate system.