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The Neurobiology and Pharmacotherapy of Posttraumatic Stress Disorder.

ABSTRACT: New approaches to the neurobiology of posttraumatic stress disorder (PTSD) are needed to address the reported crisis in PTSD drug development. These new approaches may require the field to move beyond a narrow fear-based perspective, as fear-based medications have not yet demonstrated compelling efficacy. Antidepressants, particularly recent rapid-acting antidepressants, exert complex effects on brain function and structure that build on novel aspects of the biology of PTSD, including a role for stress-related synaptic dysconnectivity in the neurobiology and treatment of PTSD. Here, we integrate this perspective within a broader framework-in other words, a dual pathology model of ( a) stress-related synaptic loss arising from amino acid-based pathology and ( b) stress-related synaptic gain related to monoamine-based pathology. Then, we summarize the standard and experimental (e.g., ketamine) pharmacotherapeutic options for PTSD and discuss their putative mechanism of action and clinical efficacy.

SUBMITTER: Abdallah CG

PROVIDER: S-EPMC6326888 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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The Neurobiology and Pharmacotherapy of Posttraumatic Stress Disorder.

Abdallah Chadi G CG Averill Lynnette A LA Akiki Teddy J TJ Raza Mohsin M Averill Christopher L CL Gomaa Hassaan H Adikey Archana A Krystal John H JH

Annual review of pharmacology and toxicology 20180914

New approaches to the neurobiology of posttraumatic stress disorder (PTSD) are needed to address the reported crisis in PTSD drug development. These new approaches may require the field to move beyond a narrow fear-based perspective, as fear-based medications have not yet demonstrated compelling efficacy. Antidepressants, particularly recent rapid-acting antidepressants, exert complex effects on brain function and structure that build on novel aspects of the biology of PTSD, including a role for ...[more]

PMID: 30216745

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Project description:Amygdala dysregulation has been shown to be central to the pathophysiology of posttraumatic stress disorder (PTSD) representing a critical treatment target. Here, amygdala downregulation was targeted using real-time fMRI neurofeedback (rt-fMRI-nf) in patients with PTSD, allowing us to examine further the regulation of emotional states during symptom provocation. Patients (n = 10) completed three sessions of rt-fMRI-nf with the instruction to downregulate activation in the amygdala, while viewing personalized trauma words. Amygdala downregulation was assessed by contrasting (a) regulate trials, with (b) viewing trauma words and not attempting to regulate. Training was followed by one transfer run not involving neurofeedback. Generalized psychophysiological interaction (gPPI) and dynamic causal modeling (DCM) analyses were also computed to explore task-based functional connectivity and causal structure, respectively. It was found that PTSD patients were able to successfully downregulate both right and left amygdala activation, showing sustained effects within the transfer run. Increased activation in the dorsolateral and ventrolateral prefrontal cortex (PFC), regions related to emotion regulation, was observed during regulate as compared with view conditions. Importantly, activation in the PFC, rostral anterior cingulate cortex, and the insula, were negatively correlated to PTSD dissociative symptoms in the transfer run. Increased functional connectivity between the amygdala- and both the dorsolateral and dorsomedial PFC was found during regulate, as compared with view conditions during neurofeedback training. Finally, our DCM analysis exploring directional structure suggested that amygdala downregulation involves both top-down and bottom-up information flow with regard to observed PFC-amygdala connectivity. This is the first demonstration of successful downregulation of the amygdala using rt-fMRI-nf in PTSD, which was critically sustained in a subsequent transfer run without neurofeedback, and corresponded to increased connectivity with prefrontal regions involved in emotion regulation during the intervention. Hum Brain Mapp 38:541-560, 2017. © 2016 Wiley Periodicals, Inc.

Project description:Background: Humans have an evolutionary need for a well-preserved internal 'clock', adjusted to the 24-hour rotation period of our planet. This intrinsic circadian timing system enables the temporal organization of numerous physiologic processes, from gene expression to behaviour. The human circadian system is tightly and bidirectionally interconnected to the human stress system, as both systems regulate each other's activity along the anticipated diurnal challenges. The understanding of the temporal relationship between stressors and stress responses is critical in the molecular pathophysiology of stress-and trauma-related diseases, such as posttraumatic stress disorder (PTSD). Objectives/Methods: In this narrative review, we present the functional components of the stress and circadian system and their multilevel interactions and discuss how traumatic stress can affect the harmonious interplay between the two systems. Results: Circadian dysregulation after trauma exposure (posttraumatic chronodisruption) may represent a core feature of trauma-related disorders mediating enduring neurobiological correlates of traumatic stress through a loss of the temporal order at different organizational levels. Posttraumatic chronodisruption may, thus, affect fundamental properties of neuroendocrine, immune and autonomic systems, leading to a breakdown of biobehavioral adaptive mechanisms with increased stress sensitivity and vulnerability. Given that many traumatic events occur in the late evening or night hours, we also describe how the time of day of trauma exposure can differentially affect the stress system and, finally, discuss potential chronotherapeutic interventions. Conclusion: Understanding the stress-related mechanisms susceptible to chronodisruption and their role in PTSD could deliver new insights into stress pathophysiology, provide better psychochronobiological treatment alternatives and enhance preventive strategies in stress-exposed populations.

Dataset Information

The Neurobiology and Pharmacotherapy of Posttraumatic Stress Disorder.

Publications

The Neurobiology and Pharmacotherapy of Posttraumatic Stress Disorder.

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