HDAC inhibitors as cognitive enhancers in fear, anxiety and trauma therapy: where do we stand?

Abstract

A novel strategy to treat anxiety and fear-related disorders such as phobias, panic and PTSD (post-traumatic stress disorder) is combining CBT (cognitive behavioural therapy), including extinction-based exposure therapy, with cognitive enhancers. By targeting and boosting mechanisms underlying learning, drug development in this field aims at designing CBT-augmenting compounds that help to overcome extinction learning deficits, promote long-term fear inhibition and thus support relapse prevention. Progress in revealing the role of epigenetic regulation of specific genes associated with extinction memory generation has opened new avenues in this direction. The present review examines recent evidence from pre-clinical studies showing that increasing histone acetylation, either via genetic or pharmacological inhibition of HDACs (histone deacetylases) by e.g. vorinostat/SAHA (suberoylanilide hydroxamic acid), entinostat/MS-275, sodium butyrate, TSA (trichostatin A) or VPA (valproic acid), or by targeting HATs (histone acetyltransferases), augments fear extinction and, importantly, generates a long-term extinction memory that can protect from return of fear phenomena. The molecular mechanisms and pathways involved including BDNF (brain-derived neurotrophic factor) and NMDA (N-methyl-D-aspartate) receptor signalling are just beginning to be revealed. First studies in healthy humans are in support of extinction-facilitating effects of HDAC inhibitors. Very recent evidence that HDAC inhibitors can rescue deficits in extinction-memory-impaired rodents indicates a potential clinical utility of this approach also for exposure therapy-resistant patients. Important future work includes investigation of the long-term safety aspects of HDAC inhibitor treatment, as well as design of isotype(s)-specific inhibitors. Taken together, HDAC inhibitors display promising potential as pharmacological adjuncts to augment the efficacy of exposure-based approaches in anxiety and trauma therapy.

The learning of fear extinction

“…Many drugs have been tried (Sun et al, 2010;Kerbage and Richa, 2013;Whittle and Singewald, 2014) and none has given yet an answer of its own comparable to that given by extinction (exposure) training by itself. That is why the search continues, and behavioral procedures to enhance extinction in the absence of drugs are being investigated (De Carvalho Myskiw et al, , 2014).…”

Plasticity of Functional MAOA Gene Methylation in Acrophobia

“…This seems to be particularly relevant for the psychotherapeutic treatment of anxiety disorders essentially entailing fear extinction (Whittle et al, 2014). …”

Valproate-Induced Neurodevelopmental Deficits inXenopus laevisTadpoles

“…This social behavior is likely a result of integration of multiple sensory and social cues (Wassersug and Hessler, 1971;Lum et al, 1982;Villinger and Waldman, 2012). We compared schooling in control and VPA-raised tadpoles: a total of 1861 inter-tadpole distances were measured for VPA-raised tadpoles and 1859 distances for matched controls.…”