PMDD: A Physician’s Perspective

DAVID R. RUBINOW, MD, is a distinguished professor and chair of psychiatry at the University of North Carolina (UNC) School of Medicine, and founding director of the UNC Center for Women’s Mood Disorders. With more than 25 years of research into the neurobehavioral effects of gonadal steroids, Dr. Rubinow has focused extensively on conditions like premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD).

BSTQ: Why is the timing of symptoms crucial to understanding and accurately diagnosing PMDD?

Dr. Rubinow: PMDD is a time-oriented not symptom-oriented diagnosis: Symptoms must consistently occur during the luteal phase of the menstrual cycle, after ovulation, and resolve during the follicular phase, after menstruation begins. This cyclical pattern is what defines PMDD more so than any specific symptoms. That said, typical symptoms include depression, sadness or hopelessness; mood swings; concentration problems; fatigue and lethargy; and feelings of being out of control. Breast swelling or tenderness, headaches, joint or muscle aches, weight gain and bloating may also occur.

BSTQ: How did you help define the criteria for PMDD?

Dr. Rubinow: In the mid-1980s, two key developments in PMDD occurred. First, a national conference aimed to standardize diagnostic procedures for PMS. Around the same time, I organized a National Institute of Mental Health (NIMH) workshop to establish formal criteria for PMS that could be used across studies. These efforts led to the development of what was initially termed late luteal phase dysphoric disorder, which included the same symptoms now recognized as PMDD.

BSTQ: You also led a study identifying genetic variants linked to PMDD. What did you discover?

Dr. Rubinow: We used gene-based haplotyping to study five genes, focusing in particular on estrogen receptors alpha and beta. We analyzed single nucleotide polymorphisms (SNPs) variations in the DNA sequence, selecting representative ones to cover large regions of each gene, which uncovered four SNPs in the fourth intron of the estrogen receptor alpha (ERα) gene that were significantly associated with PMDD. When combined into what’s called a haplotype, the association became even stronger. Interestingly, this genetic link was evident only in women who also carried a specific variant of another gene: catechol-O-methyltransferase (COMT).

BSTQ: Why is the COMT gene so significant in this context?

Dr. Rubinow: COMT helps metabolize estrogen and breaks down dopamine in the prefrontal cortex. Estrogen influences prefrontal blood flow during cognitive tasks, and other research has confirmed the prefrontal cortex’s importance in mood. The COMT variant we studied is known as Val/Val at position 158 (Valine/Valine). This form breaks down dopamine more rapidly, which may deplete dopamine in the prefrontal cortex. When combined with the identified ERα haplotype, this dopamine depletion could help explain why some women are more vulnerable to hormone-triggered mood disorders like PMDD. In short, we found a receptor for a hormone (estrogen) known to impact mood, and a gene variant (COMT) that alters how the brain processes that hormone and its downstream neurotransmitters.

BSTQ: Do these genetic insights change how PMDD should be diagnosed or treated?

Dr. Rubinow: These findings could eventually lead to new molecular targets for treatment and deepen our understanding of how mood is regulated — not just in hormone-related disorders but in mood disorders more broadly. Unlike most forms of depression, PMDD has a clear physiologic trigger: hormonal changes during the menstrual cycle. That gives us a unique opportunity to study mood regulation and potentially apply what we learn to broader psychiatric conditions.

BSTQ: What approach have you used in your clinical practice to treat PMDD?

Dr. Rubinow: Selective serotonin reuptake inhibitors are very effective for some of these disorders. Another form of treatment is ovarian suppression. (It’s not a first-line treatment, but it is a way of determining whether there is a hormonal etiology of the disorder.)

BSTQ: What do you hope healthcare providers take away from your research?

Dr. Rubinow: Always ask women of reproductive age about mood symptoms. These issues are often dismissed or misunderstood — by both patients and clinicians. Yet effective treatments do exist. The key to successful treatment is accurate diagnosis. Recognizing PMDD and other menstrual cycle-related mood disorders should be standard practice for gynecologists, psychiatrists and primary care providers alike.