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.

Trial registration: ClinicalTrials.gov NCT01018992.

Keywords: conditioning; fear conditioning; psychiatric; psychopathology; startle blink; stress.

Conflict of interest statement

JK, KG, and HM report no biomedical financial interests or potential conflicts of interest. ClinicialTrials.gov: NCT01018992

© 2019 Society for Psychophysiological Research.

Figures

Figure 1.

AX+/BX- Schematic representation of experimental design. Fear inhibition is tested by comparing the AB test trials to AX+ trials during acquisition. Inter-trial and inter-block intervals were randomized between 9 – 22 seconds as in previous work (e.g., Jovanovic et al., 2005).

Figure 2.

Average startle magnitude to NA, AX+ and BX- trials during acquisition. There was a significant increase in magnitude to the AX+ trials across all groups, F(1,54) = 10.77, p < 0.01. There was less startle to BX- compared to AX+, F(1,54) = 6.97, p = 0.01, demonstrating discrimination between threat and safety signals. There were no effects of treatment. **p ≤ 0.01

Figure 3.

Average startle magnitude to AX+ and AB trials during transfer test. There was a significant effect of treatment, in that the drug group demonstrated fear inhibition at post treatment, F(1,26) = 7.50, p = 0.01, but not prior to treatment. The placebo group showed impaired fear inhibition pre and post-treatment. **p ≤ 0.01

Figure 4.

Average inhibition score (AX+ minus AB) across Treatment and Condition. This analysis also showed that the fear inhibition score increased pre- to post-treatment in the drug group, F(1,25) = 5.20, p < 0.05, and decreased in the placebo group (F(1,26) = 4.60, p < 0.05. Larger score indicates better fear inhibition. * p ≤ 0.05