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Review
. 2019 Jan 6:59:171-189.
doi: 10.1146/annurev-pharmtox-010818-021701. Epub 2018 Sep 14.

The Neurobiology and Pharmacotherapy of Posttraumatic Stress Disorder

Chadi G Abdallah  1   2 , Lynnette A Averill  1   2 , Teddy J Akiki  1   2 , Mohsin Raza  1   2 , Christopher L Averill  1   2 , Hassaan Gomaa  1   2 , Archana Adikey  1   2 , John H Krystal  1   2
Affiliations
Review

The Neurobiology and Pharmacotherapy of Posttraumatic Stress Disorder

Chadi G Abdallah et al. Annu Rev Pharmacol Toxicol. .

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.

Keywords: PTSD; RAAD; antidepressant; chronic stress; ketamine; posttraumatic stress disorder; rapid-acting antidepressant; trauma.

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Conflict of interest statement

Conflict of Interest statement

CGA has served as a consultant and/or on advisory boards for Genentech and Janssen, and editor of Chronic Stress for Sage Publications, Inc.; JHK is a consultant for AbbVie, Inc., Amgen, Astellas Pharma Global Development, Inc., AstraZeneca Pharmaceuticals, Biomedisyn Corporation, Bristol-Myers Squibb, Eli Lilly and Company, Euthymics Bioscience, Inc., Neurovance, Inc., FORUM Pharmaceuticals, Janssen Research & Development, Lundbeck Research USA, Novartis Pharma AG, Otsuka America Pharmaceutical, Inc., Sage Therapeutics, Inc., Sunovion Pharmaceuticals, Inc., and Takeda Industries; is on the Scientific Advisory Board for Lohocla Research Corporation, Mnemosyne Pharmaceuticals, Inc., Naurex, Inc., and Pfizer; is a stockholder in Biohaven Pharmaceuticals; holds stock options in Mnemosyne Pharmaceuticals, Inc.; holds patents for Dopamine and Noradrenergic Reuptake Inhibitors in Treatment of Schizophrenia, U.S. Patent No. 5,447,948 (issued Sep 5, 1995), and Glutamate Modulating Agents in the Treatment of Mental Disorders, U.S. Patent No. 8,778,979 (issued Jul 15, 2014); and filed a patent for Intranasal Administration of Ketamine to Treat Depression. U.S. Application No. 14/197,767 (filed on Mar 5, 2014); U.S. application or Patent Cooperation Treaty international application No. 14/306,382 (filed on Jun 17, 2014); All other authors disclose no conflict of interest.

Figures

Figure 1.
Figure 1.. The “vicious cycle” of chronic stress pathology: A synaptic model of posttraumatic stress disorder (PTSD).
It is believed that traumatic stress interacts with predisposing factors to precipitate chronic stress pathology, consistent with localized synaptic loss and/or gain, leading to behavioral disruptions, which further exacerbate the chronic stress pathology. Abbreviations: FKBP5 = FK506-binding protein 5; SNP = single nucleotide polymorphism; BDNF = brain derived neurotrophic factor; HPC = hippocampus; PFC = prefrontal cortex; AG = amygdala; dACC = dorsal anterior cingulate; NAc = nucleus accumbens; dlPFC = dorsolateral PFC; VTA = ventral tegmental area; HPA = hypothalamic-pituitary axis; Glu = glutamate; The figure was adapted with permission from the Emerge Research Program (emerge.care).
Figure 2.
Figure 2.. A network-based model of posttraumatic stress disorder (PTSD).
The figure depicts the cortical representations of the salience network (SN; orange and yellow), central executive network (CEN; red), and default mode network (DMN; green). PTSD has been associated with hyperactive SN leading to heightened threat-detection and impaired modulation of the CEN and DMN. In turn, CEN and DMN deficits are associated with disruption in top-control, as well as several PTSD related symptomatology. The figure was adapted with permission from the Emerge Research Program (emerge.care).
See this image and copyright information in PMC

References

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