Posttraumatic stress disorder (PTSD) is a complex disorder associated with an
intricate biological and psychological symptom profile and various common
comorbidities. Despite the availability of various treatment strategies, PTSD is often
difficult to treat. Several researchers have proposed that impaired fear extinction is
involved in the pathophysiology of PTSD. Therefore, enhancing fear extinction using
cognitive enhancers could be a new modality for the treatment of PTSD. To date, various
cognitive enhancers that alter GABAergic, glutamatergic, dopaminergic, noradrenergic,
and cannnabinoid pathways have been investigated in animal models of fear extinction.
The present review focuses on D-cycloserine (DCS), a partial agonist of
N-methyl-D-aspartate (NMDA) receptors, and on histone deacetylase (HDAC)
inhibitors. Herein, we provide an overview of the effects of these agents, the clinical
implications and drawbacks associated with their use, and directions for future research.
Many preclinical and clinical studies of DCS have demonstrated a facilitating effect on
fear extinction. Thus, among various cognitive enhancers, DCS seems to be the most
promising agent for the treatment of PTSD. However, recent clinical studies of DCS in
PTSD have not demonstrated sufficient efficacy. Several preclinical studies have also
revealed that administration of HDAC inhibitors with exposure therapy can enhance fear
extinction. However, no clinical studies have been conducted to assess the efficacy of
HDAC inhibitors in PTSD; therefore, it is recommended that clinical trials of HDAC
inhibitors be conducted in the future.
Keywords: Cognitive enhancers, D-cycloserine, fear extinction, histone, HDAC
inhibitors, posttraumatic stress disorder, vorinostat, NMDA receptor, NR2B,
hippocampus.
