Familial Risk for Major Depression is Associated with Lower Striatal 5-HT(4) Receptor Binding

BACKGROUND: The 5-HT(4) receptor provides a novel potential target for antidepressant treatment. No studies exist to elucidate the 5-HT(4) receptor’s in vivo distribution in the depressed state or in populations that may display trait markers for major depression disorder (MDD). The aim of this study was to determine whether familial risk for MDD is associated with cerebral 5-HT(4) receptor binding as measured with [(11)C]SB207145 brain PET imaging. Familial risk is the most potent risk factor of MDD. METHODS: We studied 57 healthy individuals (mean age 36 yrs, range 20–86; 21 women), 26 of which had first-degree relatives treated for MDD. RESULTS: We found that having a family history of MDD was associated with lower striatal 5-HT(4) receptor binding (p = 0.038; in individuals below 40 years, p = 0.013). Further, we found evidence for a “risk-dose effect” on 5-HT(4) receptor binding, since the number of first-degree relatives with a history of MDD binding correlated negatively with 5-HT(4) receptor binding in both the striatum (p = 0.001) and limbic regions (p = 0.012). CONCLUSIONS: Our data suggest that the 5-HT(4) receptor is involved in the neurobiological mechanism underlying familial risk for depression, and that lower striatal 5-HT(4) receptor binding is associated with increased risk for developing MDD. The finding is intriguing considering that the 5-HT(4) receptor has been suggested to be an effective target for antidepressant treatment.