A Swedish study at Uppsala University Hospital has found that escitalopram, given at 20 mg daily during the luteal phase of the menstrual cycle, effectively reduces the symptoms of premenstrual dysphoric disorder, with the strongest impact on irritability and anger.
The menstrual cycle comprises hormonal changes that prepare the body for potential pregnancy. It is commonly divided into four phases, including the luteal phase, during which rising levels of hormones can influence both mood and physical wellbeing.
PMDD is a more severe form of premenstrual symptoms that can significantly disrupt daily life. It typically emerges in the late luteal phase and improves after menstruation starts, with emotional symptoms such as irritability, depressed mood, anxiety, mood swings and feelings of being overwhelmed, alongside potential concentration, motivation and sleep difficulties and physical symptoms.
Researchers led by Manon Dubol assessed whether treating PMDD with selective serotonin reuptake inhibitors (SSRIs) during the luteal phase could lessen symptoms, focusing on reactive aggression as a particular concern. SSRIs increase serotonin availability in the brain and are a common antidepressant treatment.
The trial took place at Uppsala University Hospital and involved 62 women with regular cycles who met PMDD criteria. The average age was about 34, and most were married or cohabiting, employed and well educated. Participants had experienced PMDD symptoms for around 11 years on average, with over three-quarters having prior PMDD treatment.
Participants were randomly assigned to two groups: 33 received 20 mg of escitalopram daily for up to 15 days in the luteal phase, while 29 received a placebo. The tablets were identical in appearance and packaging, and participants were unaware of which treatment they received.
Symptom tracking relied on the Daily Record of Severity of Problems completed via a smartphone app. To be classified as PMDD, participants had to report a 50% increase in luteal-phase symptoms compared with the follicular phase, with symptoms at least mild. The primary outcome was the overall change in PMDD symptoms, with secondary outcomes including depressed mood, anxiety, affective lability, and irritability and anger.
As part of the study, researchers used functional magnetic resonance imaging to observe brain activity in response to aggression-related stimuli. The aggression task employed was the Point Subtraction Aggression Paradigm, and participants also completed the Revised Swedish Version of the Aggression Questionnaire before and after treatment.
Results showed that those treated with escitalopram had lower PMDD symptom scores after treatment compared with the placebo group. Reductions were observed in depression, affective lability and irritability or anger, with the strongest effect seen in irritability and anger. Self-reported aggression also declined in the escitalopram group, although behavioural aggression on the aggression paradigm did not change.
Further analyses suggested that decreases in irritability and anger could partly mediate the observed drop in self-reported aggression. Neuroimaging data indicated reduced reactivity to provocation in the anterior insula among the escitalopram group, a brain region linked with threat detection and irritable or angry responses.
“This randomized 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 behavior,” the study authors concluded.
The researchers note no association between self-reported irritability/anger and aggression scores derived from the aggression task, prompting questions about the sensitivity and validity of the experimental measure in this population.
The paper, “Escitalopram and brain reactivity to aggressive stimuli in premenstrual dysphoric disorder,” was authored by Manon Dubol, Maria Gröndal, Felix Schmidt, Patrick M. Fisher, Vibe Gedsoe Frokjaer, Johan Wikström, Elias Eriksson, Inger Sundstrøm and Erika Comasco.
