Clinical trial NCT02147184: Do Serotonin Reuptake Inhibitors (SSRIs) Affect Bone Mass in Adolescents
Official title: Serotonin Reuptake Inhibitors and Bone Mineralization in Adolescents
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: The Skeletal Effects of SSRIs
Keywords: SSRI
serotonin transporter
DXA
pQCT
bone mass
adolescents
Lead sponsor: University of Iowa
Sponsor class: OTHER
Collaborators: name: National Institute of Mental Health (NIMH)
First posted: 2014-05-26
Enrollment: 287
Sex: ALL
Minimum age (years): 15
Maximum age (years): 20
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Total Body Less Head Bone Mineral Content (TBLH BMC) Z-score (Adjusted for Age-sex-height-race)
timeFrame: At baseline and every 8 months up to 2 years.
measure: Trabecular Volumetric Bone Mineral Density at the Ultradistal Radius
timeFrame: At baseline and every 4 months up to 2 years.
measure: Osteocalcin to C-terminal Telopeptide Ratio
timeFrame: At baseline and every 4 months up to 2 years.
measure: Bone-specific Alkaline Phosphatase to C-terminal Telopeptide Ratio
timeFrame: At baseline and every 4 months up to 2 years.
Secondary outcomes:
measure: Lumbar Spine Bone Mineral Density (BMD) Z-score
timeFrame: At baseline and every 8 months up to 2 years.
measure: Cortical Volumetric BMD at 20% Radius
timeFrame: At baseline and every 4 months up to 2 years.
measure: Cortical Thickness at 20% Radius
timeFrame: At baseline and every 4 months up to 2 years.
Other outcomes:
Locations:
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
Study officials:
affiliation: University of Iowa
name: Chadi Calarge, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.