Escitalopram intermittent use and brain reactivity to aggressive stimuli in premenstrual dysphoric disorder

Background: Premenstrual dysphoric disorder (PMDD) is a depressive disorder linked to the menstrual cycle, notably characterized by the cyclic occurrence of emotional distress. A core symptom is irritability or anger, whose outcome can be aggressiveness. Intermittent selective serotonin reuptake inhibitor (SSRI) treatment has shown promise in alleviating symptoms, yet the neural underpinnings of its rapid efficacy remain unknown. This randomized controlled trial aimed to evaluate the impact of intermittent SSRI treatment for PMDD on aggression-related brain function. Methods: Women with PMDD (n = 62) were randomized to receive either intermittent escitalopram (20mg/day) or placebo during the luteal phase of the menstrual cycle. Symptoms were assessed using the Daily Record of Severity of Problems. Functional magnetic resonance imaging (fMRI) was conducted in combination with the Point Subtraction Aggression Paradigm (PSAP) to evaluate neural responses to aggression-related stimuli. Results: Intermittent escitalopram treatment significantly reduced PMDD symptoms compared to placebo, particularly irritability or anger. Aggressiveness, that was positively associated with these key symptoms, diminished as an effect of treatment, with irritability mediating the relationship between treatment and aggressiveness. Reactivity to provocations was associated with lower activation of the anterior insula upon treatment with escitalopram, which also positively related to irritability. Conclusions: These findings suggest a potential neural mechanism underlying the therapeutic effects of SSRIs in PMDD and provide insights into their role, in an interplay with gonadal hormones, in modulating reactive aggression.