Escitalopram reduces anger and irritability in premenstrual dysphoric disorder, study finds

A study conducted in Sweden exploring the effects of escitalopram (20 mg per day) given during the luteal phase of the menstrual cycle found that it is effective in reducing the symptoms of premenstrual dysphoric disorder. It was particularly effective in reducing irritability and anger. Aggressiveness also diminished moderately as a result of the treatment. The paper was published in the British Journal of Psychiatry.

The menstrual cycle is a recurring series of hormonal and physical changes that prepares the female reproductive system for a possible pregnancy. It is usually divided into four main phases: menstruation, the follicular phase, ovulation, and the luteal phase. During these phases, changing levels of hormones such as estrogen and progesterone influence the ovaries, uterus, and many other systems in the body.

Many women notice physical or emotional changes in the days before menstruation, a group of symptoms commonly referred to as premenstrual symptoms. For some women, however, these symptoms are much more severe and can significantly interfere with everyday life, work, relationships, and general well-being. This more serious condition is known as premenstrual dysphoric disorder, or PMDD.

PMDD typically appears during the late luteal phase, in the week or two before menstruation. Symptoms usually improve shortly after bleeding begins. Common emotional symptoms include marked irritability, depressed mood, anxiety, mood swings, and feelings of being overwhelmed. Difficulties with concentration, motivation, and sleep can also occur. The disorder can come with physical symptoms as well. These can include fatigue, breast tenderness, bloating, headaches, and changes in appetite.

Study author Manon Dubol and her colleagues investigated the impact of treatment with selective serotonin reuptake inhibitors (SSRIs) during the luteal phase of the menstrual cycle on the symptoms of PMDD. They were particularly interested in reactive aggression, an impulsive, emotional response to a perceived threat or provocation. SSRIs are antidepressant medications that increase the availability of the neurotransmitter serotonin in the brain. They are a mainstream treatment for depression.

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The study was conducted at Uppsala University Hospital in Sweden. Study participants were 62 women with regular menstrual cycles who met diagnostic criteria for PMDD. Their average age was 34 years. Most were married or cohabiting, employed, and well-educated. On average, they reported experiencing PMDD symptoms for 11 years. Over 75% of them reported being previously treated for PMDD.

Participating women were randomly divided into two groups (33 in one group, 29 in the other). One group was to receive 20 mg of escitalopram per day for up to 15 days in the luteal phase of their menstrual cycle. The other received a placebo during the same period. Escitalopram is a widely used SSRI. It was delivered in the form of tablets. Escitalopram and placebo tablets were identical and used the same packaging and labeling. Participants were not told which treatment they were receiving.

Participants used a smartphone application to complete the Daily Record of Severity of Problems, an assessment of PMDD symptoms. Participants were considered to suffer from PMDD if their symptoms recorded in this way increased at least by 50% in the luteal phase compared to the follicular phase, and if the symptoms were at least mild. The change in these symptoms was the primary outcome study authors observed. The secondary outcomes were specific groups of PMDD symptoms: depressed mood, anxiety, affective lability (mood swings, sensitivity, being easily hurt), and irritability and anger.

Study authors also used functional magnetic resonance imaging (fMRI), a technique that maps brain activity by detecting changes in blood flow, to capture participants’ neural reactions to aggression-related stimuli. To invoke aggression in participants, study authors used the Point Subtraction Aggression Paradigm. This task measures aggression by letting participants earn points or retaliate by subtracting points from a supposed opponent who periodically takes points from them (retaliation at one’s own expense is taken as an indicator of aggression). Participants also completed a self-report assessment of aggression before and after the treatment (the Revised Swedish Version of the Aggression Questionnaire).

Results showed that participants who received escitalopram treatment had lower PMDD symptom scores after treatment compared to the placebo group. Their depression, affective lability, and irritability or anger scores were also lower. The decrease was the strongest in irritability and anger. The escitalopram group also showed moderately diminished self-reported aggression after treatment, though behavioral aggression measured by the experimental point-subtraction task did not change.

Further analyses showed that reductions in irritability and anger might be partly mediating the observed decrease in self-reported aggression. Analysis of the neuroimaging data indicated that the escitalopram group showed lower reactivity to provocation (in the experimental task) in the anterior insula, a region of the brain involved in threat detection. The activation in this area was associated with irritability or anger.

“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,” study authors concluded.

The study contributes to the scientific knowledge about the effects of escitalopram for treating PMDD. However, study authors report that they found no association between the self-reported irritability/anger and aggression scores derived from the Point Subtraction Aggression Paradigm, raising questions about the sensitivity and validity of this experimental task 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.