Increase in Serotonin Transporter Binding in Patients With Premenstrual Dysphoric Disorder Across the Menstrual Cycle: A Case-Control Longitudinal Neuroreceptor Ligand Positron Emission Tomography Imaging Study

Abstract

Background: Premenstrual dysphoric disorder (PMDD) disrupts the lives of millions of people each month. The timing of symptoms suggests that hormonal fluctuations play a role in the pathogenesis. Here, we tested whether a heightened sensitivity of the serotonin system to menstrual cycle phase underlies PMDD, assessing the relationship of serotonin transporter (5-HTT) changes with symptom severity across the menstrual cycle.

Methods: In this longitudinal case-control study, we acquired 118 [¹¹C]DASB positron emission tomography scans measuring 5-HTT nondisplaceable binding potential (BP_ND) in 30 patients with PMDD and 29 controls during 2 menstrual cycle phases (periovulatory, premenstrual). The primary outcome was midbrain and prefrontal cortex 5-HTT BP_ND. We tested whether BP_ND changes correlated with depressed mood.

Results: Linear mixed effects modeling (significant group × time × region interaction) showed a mean increase of 18% in midbrain 5-HTT BP_ND (mean [SD] periovulatory = 1.64 [0.40], premenstrual = 1.93 [0.40], delta = 0.29 [0.47]: t₂₉ = -3.43, p = .0002) in patients with PMDD, whereas controls displayed a mean 10% decrease in midbrain 5-HTT BP_ND (periovulatory = 1.65 [0.24] > premenstrual = 1.49 [0.41], delta = -0.17 [0.33]: t₂₈ = -2.73, p = .01). In patients, increased midbrain 5-HTT BP_ND correlated with depressive symptom severity (R² = 0.41, p < .0015) across the menstrual cycle.

Conclusions: These data suggest cycle-specific dynamics with increased central serotonergic uptake followed by extracellular serotonin loss underlying the premenstrual onset of depressed mood in patients with PMDD. These neurochemical findings argue for systematic testing of pre-symptom-onset dosing of selective serotonin reuptake inhibitors or nonpharmacological strategies to augment extracellular serotonin in people with PMDD.

Keywords: Female mental health; Hormone-associated mood disorders; Positron emission tomography; Premenstrual dysphoric disorder; Serotonin; Serotonin transporter.