The effect of SSRIs on fear learning: a systematic review and meta-analysis

Abstract

Rationale Selective serotonin reuptake inhibitors (SSRIs) are considered first-line medication for anxiety-like disorders such as panic disorder, generalized anxiety disorder, and post-traumatic stress disorder. Fear learning plays an important role in the development and treatment of these disorders. Yet, the effect of SSRIs on fear learning are not well known. Objective We aimed to systematically review the effect of six clinically effective SSRIs on acquisition, expression, and extinction of cued and contextual conditioned fear. Methods We searched the Medline and Embase databases, which yielded 128 articles that met the inclusion criteria and reported on 9 human and 275 animal experiments. Results Meta-analysis showed that SSRIs significantly reduced contextual fear expression and facilitated extinction learning to cue. Bayesian-regularized meta-regression further suggested that chronic treatment exerts a stronger anxiolytic effect on cued fear expression than acute treatment. Type of SSRI, species, disease-induction model, and type of anxiety test used did not seem to moderate the effect of SSRIs. The number of studies was relatively small, the level of heterogeneity was high, and publication bias has likely occurred which may have resulted in an overestimation of the overall effect sizes. Conclusions This review suggests that the efficacy of SSRIs may be related to their effects on contextual fear expression and extinction to cue, rather than fear acquisition. However, these effects of SSRIs may be due to a more general inhibition of fear-related emotions. Therefore, additional meta-analyses on the effects of SSRIs on unconditioned fear responses may provide further insight into the actions of SSRIs.

Within-patient association between emotion regulation and outcome in prolonged exposure for posttraumatic stress disorder.

“…In addition to empirically supported psychotherapies, evidence-based pharmacotherapies for PTSD, namely selective serotonin reuptake inhibitors (SSRIs; e.g., Lee et al, 2016; Stein et al, 2009), may also work by improving ER (especially in the context of trauma-related stimuli) through their impact on the serotonin (5-hydroxytryptamine) system (e.g., Lesch, 2010). Specifically, a recent meta-analysis including experimental studies in both human and animal samples found that SSRIs reduced contextual fear expression or generalization and improved extinction learning to cue (Heesbeen et al, 2023). The authors concluded that SSRIs may reduce contextual fear expression by decreasing activation in the bed nucleus of the stria terminalis, which is considered an extended component of the amygdala that is involved in processing unpredictable and sustained threat and that is often overactive in individuals with PTSD (e.g., Brinkmann et al, 2017).…”

“…The authors concluded that SSRIs may reduce contextual fear expression by decreasing activation in the bed nucleus of the stria terminalis, which is considered an extended component of the amygdala that is involved in processing unpredictable and sustained threat and that is often overactive in individuals with PTSD (e.g., Brinkmann et al, 2017). Further, SSRIs may enhance extinction learning by reducing hyperresponsivity of the amygdala (Heesbeen et al, 2023).…”