Premenstrual dysphoric disorder (PMDD) is a condition linked to the menstrual cycle and characterised by cyclic emotional distress, irritability and anger, which can disrupt social functioning. Intermittent selective serotonin reuptake inhibitor treatment is effective in alleviating symptoms, yet the neural underpinnings of its efficacy in PMDD remain unknown.

This randomised, placebo-controlled trial aimed to evaluate the impact of intermittent escitalopram treatment on PMDD symptoms and aggressiveness, and on neural responses to social provocation.

Women with PMDD were randomised to receive either intermittent escitalopram (20 mg/day) or placebo during the luteal phase. Outcomes of interest were changes in mood (assessed by the Daily Record of Severity of Problems), self-rated state aggression (measured by the Aggression Questionnaire) and neural responses to aggression-related stimuli, captured by functional magnetic resonance imaging during the Point Subtraction Aggression Paradigm.

Intermittent escitalopram treatment significantly reduced PMDD symptoms compared with placebo, in particular irritability or anger (Cohen’s d = −0.93, 95% CI [−1.48, −0.38]). Aggressiveness, which was positively associated with these symptoms (Pearson’s r = 0.33, 95% CI [0.06, 0.55]), diminished following treatment (Cohen’s d = −0.42, 95% CI [1.4 × 10−4, 0.84]), with the reduction in irritability or anger partly mediating this association (standardised indirect effect −0.32, 95% CI [−0.77, −0.03]). Escitalopram treatment was nominally associated with lower reactivity to provocation in the anterior insula (involved in salience and threat detection) (Cohen’s d = −0.34, 95% CI [−0.66, −0.02]), the activation of which was positively related to irritability or anger (Spearman’s ρ = 0.39, 95% CI [0.07, 0.64]).

This randomised controlled trial provides timely confirmation of escitalopram as an effective treatment for PMDD within a contemporary clinical context and using prospective daily symptom ratings. Functional neuroimaging suggests that modulation of serotonergic function in PMDD is related to corticolimbic circuits involved in irritability or anger and interpersonal behaviour.