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.
Highlights
Anxiety and fear-related disorders, including phobias, generalized anxiety disorder, panic disorder, post-traumatic stress disorder and obsessive compulsive disorder, are disabling, persistent and extremely prevalent disorders as epidemiology surveys estimate that up to 30% of the Western world populations will experience one or more of these disorders during their lifetime [1,2,3]
A novel strategy has emerged to treat anxiety disorder patients by combining cognitive enhancers with CBT. This strategy has been driven primarily by the translation of pre-clinical research identifying brain circuitry and molecular underpinnings of exposure-based fear extinction/CBT into clinical trials [8]. These studies have revealed that NMDA (N-methyl-D-aspartate) receptormediated signalling is one of the critical molecular mechanisms underlying exposure-based fear extinction [9,10,11] and suggest that enhancing NMDA receptor activity during CBT may act as a cognitive enhancer strategy to augment fear reductions
A growing corpus of data indicates that pharmacological adjuncts that enhance histone acetylation can act as cognitive enhancers to augment fear extinction memory (Figure 3) in addition to other forms of extinction (e.g. [47,48]). This has been assessed primarily by inhibiting HDACs as opposed to enhancing HAT activity. These findings show that fear reductions following extinction training can be facilitated by administration of various HDAC inhibitors, including vorinostat, entinostat, TSA, sodium butyrate and VPA (Table 1 and Figure 3A)
Summary
Anxiety and fear-related disorders, including phobias, generalized anxiety disorder, panic disorder, post-traumatic stress disorder and obsessive compulsive disorder, are disabling, persistent and extremely prevalent disorders as epidemiology surveys estimate that up to 30% of the Western world populations will experience one or more of these disorders during their lifetime [1,2,3].
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