Psychophysiological treatment outcomes: Corticotropin‐releasing factor type 1 receptor antagonist increases inhibition of fear‐potentiated startle in PTSD patients

Abstract

After exposure to a traumatic event, a subset of people develop post‐traumatic stress disorder (PTSD). One of the key deficits in PTSD is regulation of fear, and impaired inhibition of fear‐potentiated startle (FPS) has been identified as a potential physiological biomarker specific to PTSD. As part of a larger clinical trial, this study investigated the effects of a CRF receptor 1 antagonist, GSK561679, on inhibition of fear‐potentiated startle during a conditional discrimination fear‐conditioning paradigm, termed AX+/BX−. Prior research using this paradigm has demonstrated deficits in inhibition of conditioned fear in several PTSD populations. The randomized, double‐blind, placebo‐controlled clinical trial compared fear inhibition between female PTSD participants taking 350 mg/day GSK561679 (n = 47 pre‐ and 29 post‐treatment) and patients taking a placebo pill (n = 52 pre‐ and 30 post‐treatment) daily for 6 weeks. There was no significant difference between the two groups in their acquisition of fear or discrimination between threat and safety cues, and no pre–post‐treatment effect on these measures. However, there was a significant effect of treatment on inhibition of FPS during the AB trials in the AX+/BX− transfer test (p < 0.05). While all PTSD participants showed typical impairments in fear inhibition prior to treatment, GSK561679 enhanced fear inhibition post‐treatment, independent of clinical effects. The current study suggests that CRF receptor 1 antagonism may have specific effects within neural circuitry mediating fear inhibition responses, but not overall symptom presentation, in PTSD.

Early maturational emergence of adult-like emotional reactivity and anxiety after brief exposure to an obesogenic diet

“…The CRHR1 is abundantly expressed in fear-modulating corticolimbic circuits, including the mPFC (Steckler and Holsboer, 1999). Studies in humans and rodents indicate that CRH-CRHR1 hyper-signaling represents a candidate mechanism for PTSD risk (Bremner et al, 1997;Jovanovic et al, 2020;Rajbhandari et al, 2015;Toth et al, 2016). CRHR1 hyper-signaling alters brain structural integrity (Chen et al, 2004;Kolber et al, 2010;Toth et al, 2014) and has long-lasting consequences in stress susceptibility (Uribe-Mariño et al, 2016), mainly when it is triggered early in life (Toth et al, 2016).…”

“…Second, we reasoned that short-term exposure to an obesogenic diet would reduce the neuronal activation in corticolimbic regions implicated in fear extinction and anxiolytic effects. Finally, given the robust effects of obesogenic diets on the HPA axis and dopamine systems (Boitard et al, 2015;Khazen et al, 2019;Reyes, 2012;Sharma et al, 2013), and the modulatory actions of these factors on mPFC-amygdala circuit function (Fadok et al, 2009b;Jovanovic et al, 2010;2020;Veer et al, 2012;Whittle et al, 2016), we hypothesized that the obesogenic diet would increase the HPA tone while reducing dopamine receptor expression in the mPFC.…”

Psychophysiological approaches to understanding the impact of trauma exposure

“…There are a wide range of events and contexts that qualify as potentially traumatizing, and within each of these the “dose” of exposure (i.e., magnitude, frequency) has established associations to functional impairment (see, for instance, Neuner et al, 2004; Elbert et al, 2006; Kaltenbach, Schauer, Hermenau, Elbert, & Schalinski, 2018). As such, we selected studies that cover a wide range of trauma exposure types and trauma‐affected populations, from adolescents growing up in conflict zones ( Shaheen et al, ) or experiencing flight and displacement ( Sill, Popov, Schauer, & Elbert, 2019) to adolescent victims of childhood abuse ( Iffland et al, 2019), adult combat‐exposed veterans ( Grupe, Imhoff‐Smoth, Wielgosz, Nitschke, & Davidson, 2019; Macatee et al, 2019), African civil war survivors ( Conrad et al, 2018; Jovanovic et al, ), adults treated for fear and anxiety disorders including PTSD from various types of trauma ( Harricharan et al, 2019; Jovanovic et al, ; Sambuco, Bradley, Herring, Hillbrandt, & Lang, 2019) and childhood abuse ( Lis et al, 2019). Additionally, using a cross‐generational approach, Serpeloni, Nätt, Goncalvez de Assis, Wieling, and Elbert (2019a) studied epigenetic changes associated with domestic and intrafamilial violence in grandmothers, mothers, and adolescents.…”

“…The selection of articles further reflects the range of measures leveraged in current research on the psychophysiology of trauma exposure. Selected articles demonstrate the utility of fear‐potentiated startle ( Jovanovic et al, 2019; Lis et al, 2019), heart rate ( Grupe et al, 2019; Iffland et al, 2019), and ERPs to decode the translation of trauma exposure into PTSD symptoms ( Macatee et al, 2019; Sill et al, ), together with the power of hemodynamic imaging by means of BOLD responses during emotional scene processing ( Sambuco et al, 2019) or resting‐state connectivity ( Harricharan et al, 2019; Joshi, Duval, Kubat, & Liberzon, 2019).…”

“…However, reviews call for caution, as effects are considered modest and studies are underpowered in light of methodological challenges to verify significant effects and to capture the complexity of potential interactions. Jovanovic et al (2019) added to this state of knowledge by determining the role of corticotropin‐releasing factor (CRF) receptor 1 within the neural fear circuitry by mediating fear inhibition responses: In an elegant controlled treatment design, the CRF1 antagonist GSK561679 enhanced fear inhibition pre‐ to post‐treatment in a conditional discrimination task in female PTSD patients. This result denotes the gene–neural circuit interaction in the processing of fear‐associated stimuli and indicates a contribution to objective patterns of impaired fear inhibition in PTSD.…”