The WHO World Mental Health Survey conducted across 24 countries found a lifetime prevalence of any traumatic event of 70.4%. Establishing the diagnosis of trauma-related disorders has always been a challenge in clinical practice, as well as in academic research.
Introduction of Trauma-Related Disorders
Trauma-related disorders such as Posttraumatic stress disorder (PTSD) and acute stress disorder (ASD) are considered to be debilitating conditions, developed from exposure to traumatic events including war, mass violence, natural disasters, and accidents. The DSM-5 (American Psychiatric Association) lists 20 diagnostic criteria for PTSD divided into four clusters of symptoms: re-experience of the traumatic event; avoidance; persistent negative thoughts or feelings; trauma-related arousal and reactivity. The prevalence of PTSD in a lifetime is 11% for women and 5.5% for men. It is postulated that a dose-response relationship exists between exposure to traumatic events and the subsequent development of PTSD, indicating that prior trauma and/or multiple traumatic event exposures increase the risk of the disorder.
Neurochemical and Molecular Substrates of Fear Extinction
Trauma-related disorders are associated with excessive fear reactions triggered by specific objects, situations, or internal and external cues in the absence of any actual danger, and often include an inability to extinguish learned fear and to show adequate safety learning. Research is revealing that the activity of a number of specific intracellular signaling cascades carrying biological information from the cell surface to the nucleus, is the key to successful extinction by modulating gene transcription and ultimately promoting synaptic plasticity in extinction-relevant brain regions. Overview of pharmacological targets and signaling cascades proposed to be important in mediating synaptic plasticity underlying extinction. The formation of extinction memories requires an intricate regulatory network of signal transduction and gene transcription and translation, leading to a complex pattern of intracellular changes and long-term structural changes. Various pre-and post-synaptic membrane receptors including ionotropic and metabotropic glutamate receptors, cannabinoid receptors, 5-HT, and dopamine receptors are important targets.
Treatment of Trauma-Related Disorders
An impressive number of additional extinction augmenting drugs, acting on a wide variety of pharmacological targets, have indeed been identified. Data arising from the use of animal models displaying deficient fear extinction, reflecting patients' resistance to exposure therapy, indicate that different neurotransmitter/neurobiological signaling pathways are involved in different temporal phases of extinction. Hence, it is likely that different pharmacological approaches will be required to either induce fear reductions during extinction training or rescue/boost the consolidation of fear extinction.
The important finding that within-session fear reduction/habituation favors drug-augmented extinction rather than facilitating reconsolidation of existing fear memories has also been demonstrated in clinical trials using DCS. Moreover, multi-target approaches that simultaneously modulate the activity of diverse neurotransmitter/neurobiological systems seem to be an important option to pursue, in particular for individuals with severe extinction deficit/resistance to exposure therapy. Interestingly, in the much more well-established medical fields of infectious disease, hypertension, oncology, and similar areas, targeting multiple different mechanisms of action is also the norm, not the exception and it is also considered promising in other fields of psychiatry.
The next few years promise to produce several novel clinical approaches to treating trauma-related disorders in a more efficient and persistent way that will most likely lead to enhanced symptom remission. Progress will depend on translational research approaches and close interaction between preclinical and clinical researchers.
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