Do Serotonin Reuptake Inhibitors (SSRIs) Affect Bone Mass in Adolescents

Chadi A. Calarge287 enrolled

Overview

Building on findings from animal studies, pediatric clinical trials, epidemiologic research in adults, and on preliminary findings from the investigators' laboratory in children and adolescents, this project aims to investigate whether selective serotonin reuptake inhibitors (SSRIs), a group of widely-used psychotropics, are associated with impaired bone mineralization in youths. Establishing such an association is a first step in a process that would eventually involve developing preventative interventions. Identifying genetic factors that place certain youths at higher risks for this side effect would ultimately allow clinicians to tailor treatment to the needs and vulnerabilities of each youth, moving the field closer towards individualized medicine.

Bone mass achieved by early adulthood is a major determinant of lifetime risk for osteoporosis. Therefore, optimizing peak bone mass is crucial to avoiding bone fracture with its associated morbidity and mortality. Emerging evidence suggests that serotonin plays a central role in bone metabolism. For example, preclinical experiments have shown that bone cells express the serotonin transporter and a variety of functional serotonin receptors whose activity modulates bone turnover. Epidemiologic studies have linked SSRIs to reduced bone mineral density and increased fracture risk in the elderly. SSRIs are widely used in youths to treat a number of psychiatric disorders. However, while their short-term efficacy and safety have been established, their long-term safety remains little investigated. The investigators aim to recruit, in a 2-year prospective observational study, 15 to 20 year-old participants upon the initiation of SSRI treatment. During the study period, bone mineral density of the lumbar spine and whole body will be measured using dual-energy x-ray absorptiometry (DXA) and of the radius using peripheral quantitative computed tomography (pQCT). A detailed psychiatric assessment will be conducted to control for psychopathology, as a potential confounding factor affecting bone mineralization. Changes in psychiatric treatment during the follow up period will also be documented and accounted for. By using a group of controls, of comparable age and sex distribution, the investigators aim to evaluate 1) whether psychopathology, at baseline, is associated with low bone mass, 2) if treatment with SSRIs suppresses bone mineralization, and 3) if the discontinuation of the SSRI is followed by a restoration of bone mineral accrual. 4) Furthermore, genetic testing will investigate whether variants of the serotonin system genes moderate the effect of SSRI treatment on bone mineral density. In sum, this work aims to improve the long-term safety of psychiatric treatments in order to optimize functioning and the quality of life of those who suffer from psychiatric disorders.

Eligibility

Sex: ALLMin age: 15 YearsMax age: 20 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age 15 to 20 years old (inclusive). 2. Treatment with an SSRI, regardless of the indication, having been started within one month. This criterion does not apply to controls. SSRIs include: fluoxetine, citalopram, escitalopram, sertraline, paroxetine, and fluvoxamine. 3. Ability to provide consent. Exclusion Criteria: 1. Age- and sex-adjusted height Z-score \< -2 or \> 2. 2. Concomitant treatment with other antidepressants, psychostimulants, or mood stabilizers and antipsychotics. Treatment with benzodiazepines, low dose trazodone, alpha-2 agonists, and antihistaminergic agents will be allowed. 3. Presence of illicit drug and/or alcohol dependence. 4. Pregnancy. 5. Primary bone diseases (e.g., Paget's disease, osteogenesis imperfecta, rheumatoid arthritis). 6. Potential secondary bone disease (e.g., due to chronic inflammatory diseases, diabetes, hypo- or hyperparathyroidism, hyperthyroidism, growth hormone deficiency, and other endocrine disturbances, history of childhood cancer, or prior transplantation). 7. Chronic disorders involving a vital organ (heart, lung, liver, kidney, brain) and congenital disorders. 8. Malnutrition conditions (e.g., chronic diarrhea, inflammatory bowel disease) or lead poisoning. 9. Chronic use of drugs affecting bone metabolism (e.g., oral corticosteroids). 10. Inability to cooperate with the BMD measurements. 11. Eating disorders, due to their potential effect on BMD. 12. If a senior in high school, plan to join an out-of-state college.

Outcomes

Primary Outcomes

Total Body Less Head Bone Mineral Content (TBLH BMC) Z-score (Adjusted for Age-sex-height-race)

Whole-body dual energy x-ray absorptiometry (DXA) scan was obtained using a Hologic QDR DELPHI-4500A unit or a Hologic Discovery A unit (Hologic, Inc, Bedford, MA). The two DXA units were cross-calibrated.

Time frame: At baseline and every 8 months up to 2 years.

Trabecular Volumetric Bone Mineral Density at the Ultradistal Radius

Volumetric bone mineral density (vBMD) at the nondominant radius (4% and 20% sites) was measured, at study entry and every four months, with peripheral quantitative computed tomography (pQCT), using a Stratec XCT-2000 scanner (Stratec, Inc., Pforzheim, Germany). Image analysis was performed using the manufacturer's software package, version 6.0. pQCT scans compromised by movement were rejected. Quality control and calibration of the equipment were performed daily.