Our major research findings are as follows: 1) The first demonstration of an association between polymorphic genetic variants and premenstrual dysphoric disorder (PMD). Four single nucleotide polymorphisms in the estrogen receptor alpha gene positively associate with the disorder, and evidence for epistasis exists with the COMT gene. 2) A differential reward-related pattern of brain activation in the orbitofrontal cortex and the amygdala was observed in the luteal compared with the follicular phase of the menstrual cycle. 3) A lower DASB (a radioligand for the serotonin transporter protein) binding potential, during the luteal phase of the menstrual cycle relative to the follicular phase in several brain regions including the mid brain, pons, insula, and posterior cingulate cortices. 4) Administration of the Cambridge Neuropsychological Test Automated Battery and the Emotional Processing Battery to women with PMD identified impaired emotional coding and recognition, increased susceptibility to affective interference, and decreased capacity for emotional reappraisal and recovery compared with controls. 5) Application of chaos-based Approximate Entropy modeling to mood rating data yielded a suite of statistical descriptors that have very high sensitivity and specificity for PMD compared with recurrent brief depression and controls. 6) Administration of the 5 alpha reductase inhibitor, dutasteride, a medication that inhibits neurosteroid synthesis has no effect on symptoms of PMD. 7) We have documented for the first time the hourly change in symptom ratings in women with PMD after treatment with the selective serotonin reuptake inhibitor fluoxetine. In most women response occurs within 48-72 hours; 8) Menstrual cycle-related changes in gray matter volume (measured by Voxel-based morphometric analysis on high-resolution structural MRI) in areas of the brain regulating mood and affective adaptation including the following: subgenual cingulate cortex (increased), and in an area slightly inferior to the left amygdala (decreased) during the follicular phase compared with the luteal phase of the menstrual cycle in women. 9) Sex differences in reward-related brain activation with men activating the ventral striatum bilaterally more than women during anticipation of uncertain rewards, and women activating the anterior medial prefrontal cortex more than men at the time of reward delivery. These observations are of both theoretical and practical importance, as they both identify promising endophenotypes and suggest the physiological basis for the susceptibility to experience menstrual cycle-related mood disorders.
