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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 test 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 non-displaceable binding potential (BPND) in 30 patients with PMDD and 29 controls during two menstrual cycle phases (periovulatory, premenstrually). The primary outcome was midbrain and prefrontal cortex 5-HTT BPND. We tested whether BPND changes correlated with depressed mood.
Results
Linear mixed-effects modeling (significant group*time*region interaction) showed a mean increase of 18 percent in midbrain 5-HTT BPND (mean±SD, periovulatory=1.64±0.40 premenstrual =1.93 ±0.40, delta = 0.29 ±0.47, t(29) = -3.43, p=0.0002) in PMDD, whereas controls displayed a mean 10 percent decrease in midbrain 5-HTT BPND (periovulatory = 1.65 ±0.24 > premenstrual = 1.49 ±0.41, delta = -0.17 ±0.33, t(28) = -2.73, p=0.01). In patients, increased midbrain 5-HTT BPND correlated with depressive symptom severity (R2 = 0.41, p<0.0015) 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. These neurochemical findings argue for systematic testing of presymptom onset-dosing of selective serotonin reuptake inhibitors or non-pharmacological strategies to augment extracellular serotonin in PMDD.
