Genetic variation in the serotonin transporter and serotonin 1b receptor predicts reduced bone formation during serotonin-reuptake inhibitor treatment in older adults

Introduction: Evidence suggests an association between serotonin reuptake inhibitors (SRIs) and accelerated bone loss. SRIs and bone metabolism share a common serotonergic mechanism, generating the hypothesis that genetic variation in the serotonin system might modulate bone metabolism changes during SRI treatment. We examined functional genetic polymorphisms within serotonin receptors involved in bone metabolism, to determine whether they predict changes in bone metabolism during SRI treatment. Methods: Serum markers of bone formation (P1NP) and resorption (β-CTX) were assayed before and after treatment in 69 older adults (age ≥60) participating in a 12-week, open-label trial of the SRI venlafaxine for major depression. We also genotyped participants for putative high- vs low-expressing polymorphisms in the serotonin transporter (5HTT) and serotonin 1B receptor (5HTR1B) genes. Results: Bone formation was significantly reduced, as measured by decrease in P1NP, with administration of venlafaxine in participants with the high-expressing 5HTT genotype and those with the low expressing 5HTR1B genotype. Further analyses revealed that decrease in P1NP mostly occurred in individuals with the combination of the high-expressing 5HTT genotype and the low-expressing 5HTR1B genotype. Conclusions: These preliminary findings indicate that genetic variation in serotonin receptors predicts changes in bone metabolism during SRI use. These results require replication and clinical confirmation; if so, we have identified a genetic subgroup at high risk for deleterious bone outcomes with the use of serotonergic antidepressants.