Effects of intranasal insulin as an enhancer of fear extinction: a randomized, double-blind, placebo-controlled experimental study

Abstract

Fear-extinction based psychotherapy (exposure) is the most effective method for treating anxiety disorders. Notwithstanding, since some patients show impairments in the unlearning of fear and insufficient fear remission, there is a growing interest in using cognitive enhancers as adjuvants to exposure. As insulin plays a critical role in stress processes and acts as a memory enhancer, this study aimed to assess the capacity of intranasal insulin to augment fear extinction. A double-blind, placebo-controlled differential fear-conditioning paradigm was conducted in 123 healthy participants (63 females). Pictures of faces with neutral expressions were used as conditioned stimuli and electric shocks as unconditioned stimuli. The paradigm consisted of four phases presented on three consecutive days: acquisition (day 1), extinction (day 2), reinstatement and re-extinction (day 3). A single intranasal dose of insulin (160 IU) or placebo was applied on day 2, 45 min before fear extinction. Skin conductance response (SCR), fear-potentiated startle (FPS) and expectancy ratings were assessed. During extinction, the insulin group (independent of sex) showed a significantly stronger decrease in differential FPS in comparison with the placebo group. Furthermore, a sex-specific effect was found for SCR, with women in the insulin group showing a greater decrease of differential SCR both at early extinction and at late re-extinction. Our results provide first evidence that intranasal insulin facilitates fear extinction processes and is therefore a promising adjuvant for extinction-based therapies in anxiety and related disorders. Sex-specific effects should be taken into consideration in future studies.

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Fig. 1
Fig. 2: Differential skin conductance response during early and late extinction in the insulin and placebo group by sex.
Fig. 3: Differential fear-potentiated startle during extinction in the insulin and placebo group.
Fig. 4: Differential US expectancy during extinction, reinstatement and re-extinction in the insulin and placebo group.
Fig. 5: Differential skin conductance response during early and late re-extinction in the insulin and placebo group divided by sex.

Notes

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    Additional models were calculated to control for the effects of acquisition levels on extinction, reinstatement and re-extinction: the difference-score from the last Block of acquisition (Block 6) was added as a covariate to the analysis of physiological data, and the last trial of acquisition was added as a covariate to the analysis of expectancy ratings. Results remained largely unaltered (see Table S1).

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Acknowledgements

We gratefully acknowledge the assistance of the following students during data collection: Charlotte Fürstenberger, Danae Karamanidis-Boldt, Anna König, Annabell Montoya Martinez, Michael Richter, and Natalie Sers.

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Correspondence to Diana S. Ferreira de Sá.

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Ferreira de Sá, D.S., Römer, S., Brückner, A.H. et al. Effects of intranasal insulin as an enhancer of fear extinction: a randomized, double-blind, placebo-controlled experimental study. Neuropsychopharmacol. (2020) doi:10.1038/s41386-019-0593-3

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