The selective serotonin reuptake inhibitor sertraline alters learning from aversive reinforcements in patients with depression: evidence from a randomized controlled trial.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are first-line pharmacological treatments for depression and anxiety. However, little is known about how pharmacological action is related to cognitive and affective processes. Here, we examine whether specific reinforcement learning processes mediate the treatment effects of SSRIs. METHODS: The PANDA trial was a multicentre, double-blind, randomized clinical trial in UK primary care comparing the SSRI sertraline with placebo for depression and anxiety. Participants (N = 655) performed an affective Go/NoGo task three times during the trial and computational models were used to infer reinforcement learning processes. RESULTS: There was poor task performance: only 54% of the task runs were informative, with more informative task runs in the placebo than in the active group. There was no evidence for the preregistered hypothesis that Pavlovian inhibition was affected by sertraline. Exploratory analyses revealed that in the sertraline group, early increases in Pavlovian inhibition were associated with improvements in depression after 12 weeks. Furthermore, sertraline increased how fast participants learned from losses and faster learning from losses was associated with more severe generalized anxiety symptoms. CONCLUSIONS: The study findings indicate a relationship between aversive reinforcement learning mechanisms and aspects of depression, anxiety, and SSRI treatment, but these relationships did not align with the initial hypotheses. Poor task performance limits the interpretability and likely generalizability of the findings, and highlights the critical importance of developing acceptable and reliable tasks for use in clinical studies. FUNDING: This article presents research supported by NIHR Program Grants for Applied Research (RP-PG-0610-10048), the NIHR BRC, and UCL, with additional support from IMPRS COMP2PSYCH (JM, QH) and a Wellcome Trust grant (QH).

Interfering with fear memories by eye movement desensitization and reprocessing.

OBJECTIVE: Pharmacologic and behavioral interventions that block reconsolidation of reactivated fear memory have demonstrated only limited success in modifying stronger and long-standing fear memories. Given the efficacy of Eye Movement Desensitization and Reprocessing (EMDR) in treating PTSD, pursuit eye movements are a promising and novel intervention for studies of human memory reconsolidation. Here, we examined the efficacy of pursuit eye movements in interfering with reconsolidation of conditioned fear memories. METHODS: We conducted a 3-day differential Pavlovian fear conditioning procedure in healthy adults, using videos of biologically prepared stimuli (tarantulas), partly reinforced with electrical shocks while recording skin conductance response (SCR) as a measure of autonomic conditioned responses. Fear conditioning was performed on Day 1. On Day 2, 38 participants were randomized into groups performing pursuit eye movements either immediately after fear memory reactivation, when the fear memory was stable, or 10 min later, when the fear memory was assumed to be more labile. On Day 3, fear memory strength was assessed by SCR to both reactivated and nonreactivated fear memories. RESULTS: Strong differential conditioning to the spider stimuli were observed during both fear acquisition and fear memory reactivation. Reactivated fear memory conditioned responses of participants performing pursuit eye movements after a 10-min delay were significantly smaller in the reinstatement phase (0.16 µS; 95% CI [0.02, 0.31]). CONCLUSIONS: Pursuit eye movements were effective in reducing fear-conditioned SCR in reinstatement. This result supports the theoretical proposition that EMDR can interfere with reactivated fear memory reconsolidation.

Functional impairment in Posttraumatic Stress Disorder: A systematic review and meta-analysis.

Posttraumatic Stress Disorder (PTSD) is a serious and debilitating condition often associated with significant impairments in daily functioning. To date, research on the complexity of functional impairment in individuals with PTSD is scarce and only limited. Yet, a quantitative synthesis and comprehensive review of existing evidence is needed to better characterize the magnitude of functional impairment in PTSD in distinct domains. We conducted a systematic literature search including observational studies comparing functioning of individuals with and without PTSD. Random effects meta-analyses were performed for the different functional domains according to the WHO International Classification of Functioning, Disability and Health (ICF). The protocol followed the MOOSE guidelines for systematic reviews. A total of thirty-four studies comprising 14 206 participants were included in the study. Compared to healthy individuals, subjects with PTSD showed significant (ps < 0.001) impairments with large to very large effect sizes (ds > 1) in all domains. Subjects with, compared to without, PTSD showed significant (ps < 0.001) impairments with medium to large effect sizes (ds > 0.5) in the domains General Tasks and Demands, Mobility, Self Care, Domestic Life, Interpersonal Interactions and Relationships, Major Life Areas and Community, Social and Civic Life. Significant impairments with small to medium effect sizes in the same domains were observed comparing PTSD to other mental disorders. In conclusion, PTSD has a significant impact on most areas of daily functioning as conceptualized in the International Classification of Functioning, Disability and Health (ICF) of the WHO. Early detection and targeted treatment of functional deficits is warranted in this patient population.