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

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. Supplementary Information The online version contains supplementary material available at 10.1007/s00213-023-06333-7.

What is already known about this disease/model/intervention?Why is it important to do this review?
Fear-learning is a central process underlying the development of anxiety-like disorders, such as panic disorder, generalized anxiety disorder and post-traumatic stress disorder.Disruptions in either the acquisition or extinction of fear may result in excessive fear expression and fear generalization.Given that individuals suffering from anxiety disorders are often unable to inhibit or extinguish fear responses, treatment of anxiety disorders is mostly based on cognitive behavioural therapy (CBT), aimed at enhancing fear inhibition or fear extinction.CBT may be combined with treatment with selective serotonin re-uptake inhibitors (SSRIs) to enhance treatment response.This kind of treatment of anxiety disorders is relatively successful, yet 40% of patients remains unresponsive to treatment or suffers from residual symptoms.This means there is ample room for improvement.
Experimental animal studies focusing on fear learning are frequently used to find new ways to enhance treatment effects of CBT.For this various tests, procedures and species are used.Studies may address either acquisition or extinction, use acute or chronic dosing and test in animals following disease induction or in healthy animals.
With this systematic review we aim to objectively determine which aspects of fear learning are modulated by clinically effective SSRIs.This information may improve translation between human and animal research since it may enable informed choices for the use of particular anxiety tests and procedures.In addition, results from the systematic review may contribute to a better understanding of the role of the serotonergic system in fear acquisition and extinction learning and retrieval.Specify (a) the number of reviewers assessing the risk of bias/study quality in each study and (b) how discrepancies will be resolved Two reviewers will assess the risk of bias.In case differences in assessment occur, a third reviewer will be consulted.

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Define criteria to assess (a) the internal validity of included studies (e.g.selection, performance, detection and attrition bias) and/or (b) other study quality measures (e.g.reporting quality, power) □By use of SYRCLE's Risk of Bias tool 4 By use of SYRCLE's Risk of Bias tool, adapted as follows: -Reporting questions related to randomization/blinding □By use of CAMARADES' study quality checklist, e.g 22 □By use of CAMARADES' study quality checklist, adapted as follows: □Other criteria, namely: Collection of outcome data 39.
For each outcome measure, define the type of data to be extracted (e.g.continuous/dichotomous, unit of measurement) We expect the unit of measurement to be variable and the type of data that needs to be extracted to be continuous.

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Methods for data extraction/retrieval (e.g.first extraction from graphs using a digital screen ruler, then contacting authors) Data extraction from text, tables and graphs.Defined as largest difference between placebo treated and experimental group.If necessary, contact authors.In case data is not exactly mentioned in the text we will extract data from graphs using a digital screen ruler, if that is not possible either we will try to contact the authors 41.
Specify (a) the number of reviewers extracting data and (b) how discrepancies will be resolved One reviewer will extract the data and the second reviewer will check these extracted data.
Specify (per outcome measure) how you are planning to combine/compare the data (e.g.descriptive summary, meta-analysis) Same for acquisition learning and retrieval and extinction learning and retrieval: -Meta-analysis is limited to outcome measures reported in at least 10 independent studies to ensure sufficient statistical power.-If there is insufficient studies to perform a metaanalysis we will perform a descriptive analyse, reporting the outcome of the most effective dose (no effect, increase, decrease).Figures will be made to integrate different aspects of the reported studies.

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Specify (per outcome measure) how it will be decided whether a metaanalysis will be performed Same for acquisition learning and retrieval and extinction learning and retrieval: A subgroup analysis will be performed if five or more independent comparisons from at least three different references are included reporting the same or similar outcome measures (acquisition, extinction).
If a meta-analysis seems feasible/sensible, specify (for each outcome measure): 44.
The effect measure to be used (e.g.mean difference, standardized mean difference, risk ratio, odds ratio) Visual inspection of the funnel plot, Egger's Regression Test and Duval and Tweedie's Trim and Fill.For standardized mean differences, we will use an n-based precision estimate to avoid distortion of the funnel plots.A minimum of 15 studies (for each outcome) will be required to analyse publication bias.