SSRI_BMD: Do Serotonin Reuptake Inhibitors (SSRIs) Affect Bone Mass in Adolescents
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
|
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
- 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 Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| SSRI Group Participants within one month of starting an SSRI |
|
| Unmedicated Group No treatment with SSRIs |
Outcome Measures
Primary Outcome Measures
- Total Body Less Head Bone Mineral Content (TBLH BMC) Z-score (Adjusted for Age-sex-height-race) [At baseline and every 8 months up to 2 years.]
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.
- Trabecular Volumetric Bone Mineral Density at the Ultradistal Radius [At baseline and every 4 months up to 2 years.]
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.
- Osteocalcin to C-terminal Telopeptide Ratio [At baseline and every 4 months up to 2 years.]
Osteocalcin (ng/mL) is a bone formation marker and C-terminal telopeptide (ng/mL) a marker of bone resorption.
- Bone-specific Alkaline Phosphatase to C-terminal Telopeptide Ratio [At baseline and every 4 months up to 2 years.]
Bone-specific alkaline phosphatase (ng/mL) is a marker of bone formation while C-terminal telopeptide (ng/mL) is a marker of bone resorption.
Secondary Outcome Measures
- Lumbar Spine Bone Mineral Density (BMD) Z-score [At baseline and every 8 months up to 2 years.]
This is a Z-score adjusted for sex, age, race, and height.
- Cortical Volumetric BMD at 20% Radius [At baseline and every 4 months up to 2 years.]
- Cortical Thickness at 20% Radius [At baseline and every 4 months up to 2 years.]
This is cortical thickness as measured by pQCT.
Other Outcome Measures
- 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]
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Age 15 to 20 years old (inclusive).
-
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.
-
Ability to provide consent.
Exclusion Criteria:
-
Age- and sex-adjusted height Z-score < -2 or > 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.
-
Presence of illicit drug and/or alcohol dependence.
-
Pregnancy.
-
Primary bone diseases (e.g., Paget's disease, osteogenesis imperfecta, rheumatoid arthritis).
-
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).
-
Chronic disorders involving a vital organ (heart, lung, liver, kidney, brain) and congenital disorders.
-
Malnutrition conditions (e.g., chronic diarrhea, inflammatory bowel disease) or lead poisoning.
-
Chronic use of drugs affecting bone metabolism (e.g., oral corticosteroids).
-
Inability to cooperate with the BMD measurements.
-
Eating disorders, due to their potential effect on BMD.
-
If a senior in high school, plan to join an out-of-state college.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Iowa Hospitals and Clinics | Iowa City | Iowa | United States | 52242 |
Sponsors and Collaborators
- Chadi A. Calarge
- National Institute of Mental Health (NIMH)
Investigators
- Principal Investigator: Chadi Calarge, MD, University of Iowa
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 201109866
- R01MH090072-01A1
Study Results
Participant Flow
| Recruitment Details | Between 09/2010 and 12/2014, 287 participants were recruited into this longitudinal observational study, from outpatient and inpatient clinical settings as well as by advertisement and word of mouth. However, 23 of them either did not complete their intake visit or had to be excluded due to discovery of exclusionary conditions. |
|---|---|
| Pre-assignment Detail | within one month of starting a SSRI or taking no psychotropics |
| Arm/Group Title | SSRI Group | Unmedicated Group |
|---|---|---|
| Arm/Group Description | Participants within one month of starting an SSRI | No treatment with SSRIs |
| Period Title: Overall Study | ||
| STARTED | 127 | 137 |
| COMPLETED | 78 | 110 |
| NOT COMPLETED | 49 | 27 |
Baseline Characteristics
| Arm/Group Title | SSRI Group | Unmedicated Group | Total |
|---|---|---|---|
| Arm/Group Description | Participants within one month of starting an SSRI | No treatment with SSRIs | Total of all reporting groups |
| Overall Participants | 127 | 137 | 264 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
18.8
(1.7)
|
19.0
(1.5)
|
18.9
(1.6)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
83
65.4%
|
76
55.5%
|
159
60.2%
|
| Male |
44
34.6%
|
61
44.5%
|
105
39.8%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
11
8.7%
|
11
8%
|
22
8.3%
|
| Not Hispanic or Latino |
116
91.3%
|
126
92%
|
242
91.7%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
2
1.6%
|
2
1.5%
|
4
1.5%
|
| Asian |
4
3.1%
|
11
8%
|
15
5.7%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
7
5.5%
|
5
3.6%
|
12
4.5%
|
| White |
114
89.8%
|
119
86.9%
|
233
88.3%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (Count of Participants) | |||
| United States |
127
100%
|
137
100%
|
264
100%
|
Outcome Measures
| Title | Total Body Less Head Bone Mineral Content (TBLH BMC) Z-score (Adjusted for Age-sex-height-race) |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| These are the starting sample size but the figures below reflect participant attrition. |
| Arm/Group Title | SSRI Group | Unmedicated Group |
|---|---|---|
| Arm/Group Description | Participants within one month of starting an SSRI | No treatment with SSRIs |
| Measure Participants | 127 | 137 |
| Baseline |
0.35
(0.84)
|
0.43
(0.90)
|
| 8 Months |
0.36
(0.84)
|
0.44
(0.92)
|
| 16 Months |
0.32
(0.87)
|
0.47
(0.90)
|
| 24 Months |
0.32
(0.90)
|
0.41
(0.87)
|
| Title | Trabecular Volumetric Bone Mineral Density at the Ultradistal Radius |
|---|---|
| Description | 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. |
| Time Frame | At baseline and every 4 months up to 2 years. |
Outcome Measure Data
| Analysis Population Description |
|---|
| This was the starting sample size. However, the figures below reflect participant attrition and exclusion of scans due to movement artifact. |
| Arm/Group Title | SSRI Group | Unmedicated Group |
|---|---|---|
| Arm/Group Description | Participants within one month of starting an SSRI | No treatment with SSRIs |
| Measure Participants | 127 | 137 |
| Baseline |
213.7
(37.7)
|
220.7
(35.0)
|
| 4 Months |
212.9
(40.7)
|
220.0
(37.8)
|
| 8 Months |
217.9
(40.2)
|
220.8
(39.5)
|
| 12 Months |
213.6
(42.9)
|
218.9
(38.9)
|
| 16 Months |
216.5
(40.3)
|
220.9
(41.1)
|
| 20 Months |
213.6
(41.9)
|
218.7
(39.4)
|
| 24 Months |
209.1
(40.48)
|
221.7
(37.1)
|
| Title | Osteocalcin to C-terminal Telopeptide Ratio |
|---|---|
| Description | Osteocalcin (ng/mL) is a bone formation marker and C-terminal telopeptide (ng/mL) a marker of bone resorption. |
| Time Frame | At baseline and every 4 months up to 2 years. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The figures below may be lower based on availability of serum, performance of the assay, and premature attrition. |
| Arm/Group Title | SSRI Group | Unmedicated Group |
|---|---|---|
| Arm/Group Description | Participants within one month of starting an SSRI | No treatment with SSRIs |
| Measure Participants | 127 | 137 |
| Baseline |
49.1
(16.4)
|
50.4
(18.7)
|
| 4 Months |
53.9
(33.6)
|
47.2
(17.3)
|
| 8 Months |
49.7
(17.1)
|
49.1
(18.2)
|
| 12 Months |
53.4
(22.8)
|
47.2
(18.1)
|
| 16 Months |
51.9
(17.9)
|
50.3
(20.9)
|
| 20 Months |
46.8
(14.2)
|
50.3
(20.8)
|
| 24 Months |
54.5
(21.7)
|
48.0
(16.5)
|
| Title | Bone-specific Alkaline Phosphatase to C-terminal Telopeptide Ratio |
|---|---|
| Description | Bone-specific alkaline phosphatase (ng/mL) is a marker of bone formation while C-terminal telopeptide (ng/mL) is a marker of bone resorption. |
| Time Frame | At baseline and every 4 months up to 2 years. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The figures below might be less than the stated numbers above depending on availability of serum samples, the performance of the assay, and premature attrition. |
| Arm/Group Title | SSRI Group | Unmedicated Group |
|---|---|---|
| Arm/Group Description | Participants within one month of starting an SSRI | No treatment with SSRIs |
| Measure Participants | 127 | 137 |
| Baseline |
49.4
(16.4)
|
50.3
(18.6)
|
| 4 Months |
54.8
(34.4)
|
46.5
(16.3)
|
| 8 Months |
51.9
(16.9)
|
48.9
(16.1)
|
| 12 Months |
54.2
(22.6)
|
47.2
(18.1)
|
| 16 Months |
52.7
(18.7)
|
51.4
(21.1)
|
| 20 Months |
46.8
(14.3)
|
50.0
(20.9)
|
| 24 Months |
56.0
(22.4)
|
47.3
(14.9)
|
| Title | Lumbar Spine Bone Mineral Density (BMD) Z-score |
|---|---|
| Description | This is a Z-score adjusted for sex, age, race, and height. |
| Time Frame | At baseline and every 8 months up to 2 years. |
Outcome Measure Data
| Analysis Population Description |
|---|
| This was the initial sample size per group but the figures below reflect attrition or data excluded due to artifact. |
| Arm/Group Title | SSRI Group | Unmedicated Group |
|---|---|---|
| Arm/Group Description | Participants within one month of starting an SSRI | No treatment with SSRIs |
| Measure Participants | 127 | 137 |
| Baseline |
-0.00
(1.03)
|
0.09
(1.09)
|
| 8 Months |
0.01
(1.06)
|
0.13
(1.09)
|
| 16 Months |
-0.02
(1.19)
|
0.11
(1.17)
|
| 24 Months |
0.03
(1.18)
|
0.09
(1.06)
|
| Title | Cortical Volumetric BMD at 20% Radius |
|---|---|
| Description | |
| Time Frame | At baseline and every 4 months up to 2 years. |
Outcome Measure Data
| Analysis Population Description |
|---|
| This was the original sample size per group but the figures below reflect attrition and data exclusion due to movement artifacts. |
| Arm/Group Title | SSRI Group | Unmedicated Group |
|---|---|---|
| Arm/Group Description | Participants within one month of starting an SSRI | No treatment with SSRIs |
| Measure Participants | 127 | 137 |
| Baseline |
1155.6
(33.0)
|
1156.2
(34.5)
|
| 4 Months |
1159.8
(29.9)
|
1161.7
(29.5)
|
| 8 Months |
1163.1
(26.7)
|
1164.7
(28.5)
|
| 12 Months |
1168.3
(26.5)
|
1166.8
(27.1)
|
| 16 Months |
1170.1
(22.6)
|
1169.5
(24.9)
|
| 20 Months |
1172.8
(27.2)
|
1173.1
(22.7)
|
| 24 Months |
1173.4
(23.0)
|
1170.5
(25.4)
|
| Title | Cortical Thickness at 20% Radius |
|---|---|
| Description | This is cortical thickness as measured by pQCT. |
| Time Frame | At baseline and every 4 months up to 2 years. |
Outcome Measure Data
| Analysis Population Description |
|---|
| The figures below may be lower than the overall numbers above due to exclusions for movement artifacts and premature drop outs. |
| Arm/Group Title | SSRI Group | Unmedicated Group |
|---|---|---|
| Arm/Group Description | Participants within one month of starting an SSRI | No treatment with SSRIs |
| Measure Participants | 127 | 137 |
| Baseline |
2.70
(0.34)
|
2.80
(0.35)
|
| 4 Months |
2.68
(0.32)
|
2.80
(0.34)
|
| 8 Months |
2.72
(0.34)
|
2.83
(0.36)
|
| 12 Months |
2.69
(0.33)
|
2.82
(0.36)
|
| 16 Months |
2.72
(0.31)
|
2.81
(0.36)
|
| 20 Months |
2.72
(0.33)
|
2.79
(0.35)
|
| 24 Months |
2.67
(0.30)
|
2.84
(0.38)
|
| Title | 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 |
|---|---|
| Description | |
| Time Frame | 2 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
Adverse Events
| Time Frame | 2 years. | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | This was not a clinical intervention. Adverse events were simply related to participating in a study. | |||
| Arm/Group Title | SSRI Group | Unmedicated Group | ||
| Arm/Group Description | Participants within one month of starting an SSRI | No treatment with SSRIs | ||
All Cause Mortality |
||||
| SSRI Group | Unmedicated Group | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/127 (0%) | 0/137 (0%) | ||
Serious Adverse Events |
||||
| SSRI Group | Unmedicated Group | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/127 (0%) | 1/137 (0.7%) | ||
| Cardiac disorders | ||||
| Fainting | 0/127 (0%) | 0 | 1/137 (0.7%) | 1 |
Other (Not Including Serious) Adverse Events |
||||
| SSRI Group | Unmedicated Group | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 19/127 (15%) | 27/137 (19.7%) | ||
| Blood and lymphatic system disorders | ||||
| Multiple blood draws required | 10/127 (7.9%) | 10 | 17/137 (12.4%) | 17 |
| Cardiac disorders | ||||
| Lightheadedness | 6/127 (4.7%) | 7 | 9/137 (6.6%) | 9 |
| Syncope | 3/127 (2.4%) | 3 | 1/137 (0.7%) | 1 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr. Chadi Calarge |
|---|---|
| Organization | Baylor College of Medicine |
| Phone | 832-824-4764 |
| chadi.calarge@bcm.edu |
- 201109866
- R01MH090072-01A1