Measurement and modulation of prefrontal GABA* levels in adolescent girls with premenstrual dysphoric disorder (PMDD): a proof-of-concept study

PROJECT CONTEXT

Premenstrual Dysphoric Disorder (PMDD) is a severe mood disorder that appears during the luteal phase of the menstrual cycle, affecting approximately 1.2 to 6.4% of women. It manifests as emotional instability, depressed mood, anxiety and irritability, leading to significant distress.

This disorder affects between 20,000 and 90,000 young girls and women in Canada. This new project, a first in this field, aims to explore innovative therapeutic approaches to help these teenagers, who often continue to suffer from PMDD into adulthood.
PMDD is strongly associated with a deterioration in quality of life, and is a major risk factor for suicidal thoughts and attempts.

Selective serotonin reuptake inhibitors (SSRIs) are often used to treat PMDD. Although these drugs are effective, their action may not be limited to serotonin.
Another hypothesis concerning PMDD is that it may be linked to a substance called allopregnanolone (ALLO), derived from the hormone progesterone. ALLO plays a role in the brain’s GABA* system. SSRIs used to treat PMDD could alter the conversion of progesterone to ALLO, thereby influencing the functioning of the brain’s GABA system.

^{*GABA (gamma-aminobutyric acid) is an amino acid and an important neurotransmitter in the body. It transmits chemical messages in the brain at high speed. Unlike other neurotransmitters such as serotonin and dopamine, GABA is inhibitory, which means it reduces central nervous system activity and acts as a brake on certain brain signals, such as anxiety and hyperactivation.}

Here are a few elements supporting this theory:

• Girls and women with PMDD have lower levels of GABA.
• GABA is reduced in certain areas of the brain during PMDD symptoms.
• Sepranolone, a drug that blocks certain GABA receptors, helps relieve PMDD symptoms.

Although SSRIs are widely used, their efficacy is sometimes questioned. An approach that directly targets the neurosteroid-GABA system could offer a promising alternative.

THE PROJECT

The research project focuses on premenstrual dysphoric disorder (PMDD), which occurs in some women before their period and can make people very sad, anxious, and even prevent them from doing normal daily activities, such as going to school. This project explores a new way of helping these girls and women using a technology called repetitive transcranial magnetic stimulation (rTMS). rTMS works a bit like a magnet that sends impulses into the brain to change the way it works.

The proposed study is an open feasibility and proof-of-concept study involving 20 adolescent girls aged 14 to 18 with PMDD. Diagnosis will be verified by DSM-5 symptom assessment over two menstrual cycles.

The main evaluation criteria will be the measurement of daily symptoms, as well as GABA levels in the dorsolateral prefrontal cortex (DLPFC). CPFDL before and after rTMS intervention. rTMS will be administered during the luteal phase (the period following ovulation to the onset of menses) of three menstrual cycles, at 37.5 minutes per session, five days a week, over two consecutive weeks.

The assumptions are as follows:

• High-frequency rTMS on the left DLPFC once a day, 5 days a week for two premenstrual weeks will reduce premenstrual dysphoric disorder symptoms.
• GABA levels in the DLPFC will increase after rTMS intervention.

The aim of this feasibility study is :

• Use magnetic resonance spectroscopy (MRS) to measure GABA concentration in the dorsolateral prefrontal cortex (DLPFC).
• To test repetitive transcranial magnetic stimulation (rTMS)* to reduce PMDD symptoms in adolescent girls.

^{*rTMS Repetitive Transcranial Magnetic Stimulation: This is a non-invasive technique, renowned for its safety, which generates targeted electrical currents in the brain and induces lasting changes in cortical excitability. It is already used in the treatment of major depressive disorders, including in adolescents, and was approved by Health Canada in 2002 for this indication.}

PROJECT ORIGINALITY

The project aims to treat PMDD by directly targeting the GABAergic system via rTMS, an approach that has never been used to date in this context.

In addition, the use of rTMS to measure GABA levels will provide objective data on the neurochemical changes associated with PMDD and its treatment, making it possible to test the neurosteroid-GABA hypothesis.

Finally, the project specifically targets adolescent girls, an understudied population in PMDD research.

POTENTIAL IMPACT ON ADOLESCENT HEALTH

According to current prevalence-based estimates, between 20,000 and 90,000 Canadian teenagers suffer from PMDD, and over 300,000 women of childbearing age are affected in Canada. Ultimately, this research project could potentially transform the management of PMDD in adolescent girls by establishing a more effective approach than current treatments, which are associated with side effects and the stigma attached to taking antidepressant medication.

Improving PMDD symptoms would contribute to a better quality of life for affected teenagers, reducing school absences and lowering the risk of suicidal thoughts.

In short, this project has the potential to provide early and specific intervention, promoting the mental health and well-being of adolescent girls, and laying the foundations for innovative therapeutic approaches in this population.

POTENTIAL IMPACT ON STUDENT TRAINING

The project presented constitutes ample work for the training of two graduate students, in addition to providing an internship opportunity for 1-2 undergraduate students. By participating in a cutting-edge study using MRS and rTMS, the students and trainee will acquire practical skills in the use of advanced imaging techniques, fostering their development as young investigators in the field of pediatric neuroscience.

PATIENT-PARTNER INVOLVEMENT

With the agreement of her parents/legal guardians, a young woman living with PMDD will be asked to advise the researchers in setting up the study, to offer a personal perspective on the most important elements of PMDD, and to support them in developing the most relevant recruitment material possible for adolescent girls. A 15-year-old from Sherbrooke has already expressed an interest in this role.

POTENTIAL LEVERAGE

The research theme is clearly under-studied, affects a large number of people, and lies at the crossroads of pediatrics, clinical neuroscience and women’s health. This funding will help to obtain pilot data for an eventual application to the CIHR, as well as cementing collaboration between two laboratories at the CRCHUS and CRHSJ through project management and student supervision.