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

Serotonin Reuptake Inhibitors and Bone Mineralization in Adolescents

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.

Study Overview

• Status: Completed
• Conditions: The Skeletal Effects of SSRIs

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 287

Contacts and Locations

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 20 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Patients within one month of initiating treatment with SSRIs will be recruited, regardless of the indication for SSRIs.

Unmedicated controls will be also recruited.

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
SSRI Group; Participants within one month of starting an SSRI
Unmedicated Group; No treatment with SSRIs

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	At baseline and every 4 months up to 2 years.
Osteocalcin to C-terminal Telopeptide Ratio	Osteocalcin (ng/mL) is a bone formation marker and C-terminal telopeptide (ng/mL) a marker of bone resorption.	At baseline and every 4 months up to 2 years.
Bone-specific Alkaline Phosphatase to C-terminal Telopeptide Ratio	Bone-specific alkaline phosphatase (ng/mL) is a marker of bone formation while C-terminal telopeptide (ng/mL) is a marker of bone resorption.	At baseline and every 4 months up to 2 years.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lumbar Spine Bone Mineral Density (BMD) Z-score	This is a Z-score adjusted for sex, age, race, and height.	At baseline and every 8 months up to 2 years.
Cortical Volumetric BMD at 20% Radius		At baseline and every 4 months up to 2 years.
Cortical Thickness at 20% Radius	This is cortical thickness as measured by pQCT.	At baseline and every 4 months up to 2 years.

Other Outcome Measures

Outcome Measure	Time Frame
The Moderating Effect of the Short Allele of the Serotonin Transporter-Linked Polymorphic Region (5HTTLPR) Gene on the Association Between SSRI Use and the Primary Outcomes	2 years

Collaborators and Investigators

• Sponsor: Chadi A. Calarge
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Chadi Calarge, MD, University of Iowa

Publications and helpful links

General Publications

• Martins LB, Delevati Colpo G, Calarge CA, Teixeira AL. Inflammatory Markers Profile in Older Adolescents During Treatment with Selective Serotonin Reuptake Inhibitors. J Child Adolesc Psychopharmacol. 2021 Aug;31(6):439-444. doi: 10.1089/cap.2020.0140. Epub 2021 Jun 24.
• Mellick WH, Mills JA, Kroska EB, Calarge CA, Sharp C, Dindo LN. Experiential Avoidance Predicts Persistence of Major Depressive Disorder and Generalized Anxiety Disorder in Late Adolescence. J Clin Psychiatry. 2019 Oct 22;80(6):18m12265. doi: 10.4088/JCP.18m12265.
• Dindo LN, Recober A, Haddad R, Calarge CA. Comorbidity of Migraine, Major Depressive Disorder, and Generalized Anxiety Disorder in Adolescents and Young Adults. Int J Behav Med. 2017 Aug;24(4):528-534. doi: 10.1007/s12529-016-9620-5.
• Deumic E, Butcher BD, Clayton AD, Dindo LN, Burns TL, Calarge CA. Sexual Functioning in Adolescents With Major Depressive Disorder. J Clin Psychiatry. 2016 Jul;77(7):957-62. doi: 10.4088/JCP.15m09840.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2010
• Primary Completion (Actual): April 1, 2016
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: April 2, 2014
• First Submitted That Met QC Criteria: May 21, 2014
• First Posted (Estimated): May 26, 2014

Study Record Updates

• Last Update Posted (Actual): June 28, 2023
• Last Update Submitted That Met QC Criteria: June 8, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: adolescents; DXA; bone mass; SSRI; serotonin transporter; pQCT
• Other Study ID Numbers: 201109866; R01MH090072-01A1 (U.S. NIH Grant/Contract)