Context: The pathobiology of the metabolic syndrome remains unclear. The central nervous system is likely to be involved via regulation of eating, physical activity, BP and metabolism.

Objective: to test the hypothesis that low central serotonergic activity is associated with the metabolic syndrome

Design, setting, participants: cross-sectional study of 345 healthy community volunteers, aged 30-55 yr, not taking medications for hypertension, lipid disorders or diabetes

Outcome measures: Central serotonergic responsivity was assessed with the intravenous citalopram challenge test. Serum prolactin area-under-the-curve (AUC) over 150 min was calculated and all analyses were adjusted for age, sex, plasma citalopram concentration and baseline prolactin. The metabolic syndrome was defined according to the National Cholesterol Education Program (NCEP) and International Diabetes Federation (IDF) criteria. Insulin resistance was estimated by Homeostasis Model Assessment.

Results: Compared with other individuals, persons meeting either NCEP or IDF criteria for the metabolic syndrome had lower mean prolactin responses (P < 0.05 for both). Using logistic regression, a decrease in prolactin AUC of 1 SD (-13.6 ng/ml*hr) more than doubled the odds of having the metabolic syndrome (NCEP criteria: odds ratio (95%CI) =2.38 (1.14 -4.97); p= 0.02; IDF criteria: 2.80 (1.48 -5.30); p = 0.002). Finally, prolactin AUC was negatively associated with insulin resistance ( = -0.03, P = 0.02).

Conclusions: Corroborating prior evidence, the metabolic syndrome was associated with diminished brain serotonergic activity as reflected in a comparative blunting of the prolactin response to a selective serotonergic challenge. This association may have implications for the etiology, prevention and treatment of the metabolic syndrome.