Risperidone-induced Hyperprolactinemia
Conditions
Keywords
Risperidone, hyperprolactinemia, children, adolescents, antipsychotics, prevention, calcium, vitamin D, Risperidone-induced hyperprolactinemia
Brief summary
The purpose of this study is to determine whether calcium and vitamin D supplementation, over a nine-month period, optimizes bone mineralization in boys with risperidone-induced hyperprolactinemia. We hypothesize that, by the end of the stuy, children in the supplementation group will have higher bone mineral density compared to those in the placebo group.
Interventions
Calcium carbonate 625mg and vitamin D 200IU will be administered, orally, twice a day for a nine-month period.
OTHERPlacebo
Sponsors
National Institute of Mental Health (NIMH)
Children's Miracle Network
Chadi A. Calarge
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
5 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
1. Males (age range: 5-17yo; inclusive), in treatment with risperidone for ≥ one year. 2. The participants must have two measurements of prolactin ≥ 18.4 ng/ml, obtained within a week. 3. IQ \> 35-40 (≥ Moderate intellectual disability). 4. An adult parent/guardian must be available to provide consent and dispense study medication.
Exclusion criteria
1. Chronic disorders involving a vital organ (heart, lung, liver, kidney, brain), metabolic diseases (e.g., diabetes, hypo- or hyperparathyroidism, hypo- or hyperthyroidism, growth hormone deficiency), other skeletal diseases (e.g., Paget's disease, osteogenesis imperfecta, rheumatoid arthritis), chronic use of drugs affecting bone metabolism (e.g., corticosteroids), and malnutrition conditions (e.g., chronic diarrhea, inflammatory bowel disease), congenital disorders, or lead poisoning. 2. Participants receiving calcium or multivitamins in the previous three months. 3. A history of renal calculi and fasting random urine calcium/creatinine ratio \> 0.2 or any other medical disorder that contraindicates the use of calcium or vitamin D (e.g., hypercalcemic states, hypercoagulability disorders, vitamin D toxicity, malabsorption syndrome, or hypersensitivity to vitamin D products). 4. Laboratory values outside the normal range, except for prolactin, unless the deviations were not clinically significant (e.g. TSH \< 10 μIU/ml (76)). 5. Inability to cooperate with the BMD measurements. 6. Bilateral wrist or forearm fractures. 7. Eating disorders. 8. Non-compliance with the prescribed psychiatric treatment as reflected by an undetectable combined risperidone and 9-hydroxy risperidone blood concentration. 9. Plans to move out of State within the next 9 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Trabecular Bone Mineral Density in the Ultradistal Radius | 36 weeks | Peripheral quantitative computed tomography (pQCT) scan was obtained at the 4% and 20% sites of the nondominant radius to estimate trabecular and cortical BMD, respectively. A Stratec XCT-2000 scanner, software version 6.0 (Stratec, Inc., Pforzheim, Germany),was used. Trabecular BMD was measured as the mean density of the 85% central area of the bone's cross-section. Outcomes were measured at baseline, 18 weeks, and 36 weeks later. |
| Total Body Bone Mineral Content | 36 weeks | Outcomes were measured at baseline, 18 weeks, and 36 weeks later. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cortical Thickness | 36 weeks | This was measured at the 20% radius site. |
| Periosteal Circumference | 36 weeks | This was measured at the 20% radius site. |
| Bone Strength Index, mg2/mm4 | 36 weeks | Measured at the 4% radius site. |
| Polar Section Modulus | 36 weeks | This was measured at the 20% radius site. |
| Endosteal Circumference | 36 weeks | This was measured at the 20% radius site. |
| Cortical Bone Mineral Density | 36 weeks | This was measured at the 20% radius site. |
Countries
United States
Participant flow
Recruitment details
Between 02/2009 and 11/2013, medically-healthy 5 to 17 year-old risperidone-treated boys were enrolled, via screening of the electronic medical records, referrals, and word of mouth.
Pre-assignment details
Participants were required to have been in treatment with risperidone for at least one year. They should have had a prolactin concentration ≥ 18.4 ng/ml on two occasions, within one week.
Participants by arm
| Arm | Count |
|---|---|
| Calcium+VitD Calcium and Vitamin D: Calcium carbonate 625mg and vitamin D 200IU will be administered, orally, twice a day for a nine-month period.
I labelled the intervention type as drug, even though dietary supplement would be more appropriate as the system sent the following error message:
ERROR: An IND/IDE study must have at least one intervention of type: Drug, Device, Biological/Vaccine, Radiation or Genetic. | 23 |
| Placebo Calcium and Vitamin D: Calcium carbonate 625mg and vitamin D 200IU will be administered, orally, twice a day for a nine-month period.
I labelled the intervention type as drug, even though dietary supplement would be more appropriate as the system sent the following error message:
ERROR: An IND/IDE study must have at least one intervention of type: Drug, Device, Biological/Vaccine, Radiation or Genetic. | 24 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Urinary Calcium/Creatinine > 0.2 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Calcium+VitD | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 10.8 years STANDARD_DEVIATION 3 | 11.5 years STANDARD_DEVIATION 3 | 12.1 years STANDARD_DEVIATION 3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 45 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 6 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 21 Participants | 40 Participants | 19 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 23 Participants | 47 Participants | 24 Participants |
| Total Body Less Head Bone Mineral Content Z-score | 0.10 Z-score STANDARD_DEVIATION 0.79 | 0.11 Z-score STANDARD_DEVIATION 0.73 | 0.12 Z-score STANDARD_DEVIATION 0.68 |
| Trabecular Bone Mineral Density, mg/cm3 | 192.9 mg/cm3 STANDARD_DEVIATION 31.1 | 195.0 mg/cm3 STANDARD_DEVIATION 37.5 | 197.2 mg/cm3 STANDARD_DEVIATION 43.9 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 24 |
| other Total, other adverse events | 11 / 23 | 8 / 24 |
| serious Total, serious adverse events | 0 / 23 | 0 / 24 |
Outcome results
Primary
Total Body Bone Mineral Content
Outcomes were measured at baseline, 18 weeks, and 36 weeks later.
Time frame: 36 weeks
Population: Numbers below reflect attrition.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Calcium+VitD | Total Body Bone Mineral Content | At Baseline | 0.10 Z score (age-sex-height-race specific) | Standard Deviation 0.79 |
| Calcium+VitD | Total Body Bone Mineral Content | At 18 Weeks | 0.24 Z score (age-sex-height-race specific) | Standard Deviation 0.81 |
| Calcium+VitD | Total Body Bone Mineral Content | At 36 Weeks | 0.20 Z score (age-sex-height-race specific) | Standard Deviation 0.86 |
| Placebo | Total Body Bone Mineral Content | At Baseline | 0.12 Z score (age-sex-height-race specific) | Standard Deviation 0.68 |
| Placebo | Total Body Bone Mineral Content | At 18 Weeks | 0.23 Z score (age-sex-height-race specific) | Standard Deviation 0.76 |
| Placebo | Total Body Bone Mineral Content | At 36 Weeks | 0.17 Z score (age-sex-height-race specific) | Standard Deviation 0.78 |
Primary
Trabecular Bone Mineral Density in the Ultradistal Radius
Peripheral quantitative computed tomography (pQCT) scan was obtained at the 4% and 20% sites of the nondominant radius to estimate trabecular and cortical BMD, respectively. A Stratec XCT-2000 scanner, software version 6.0 (Stratec, Inc., Pforzheim, Germany),was used. Trabecular BMD was measured as the mean density of the 85% central area of the bone's cross-section. Outcomes were measured at baseline, 18 weeks, and 36 weeks later.
Time frame: 36 weeks
Population: The number at baseline is smaller than the randomized number because bone scans with movement artifact were discarded. At late time points, the sample size reflects both attrition and exclusion due to movement artifact.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Calcium+VitD | Trabecular Bone Mineral Density in the Ultradistal Radius | Baseline | 192.9 mg/cm^3 | Standard Deviation 31.1 |
| Calcium+VitD | Trabecular Bone Mineral Density in the Ultradistal Radius | At 18 Weeks | 191.0 mg/cm^3 | Standard Deviation 38.4 |
| Calcium+VitD | Trabecular Bone Mineral Density in the Ultradistal Radius | At 36 Weeks | 195.7 mg/cm^3 | Standard Deviation 36.9 |
| Placebo | Trabecular Bone Mineral Density in the Ultradistal Radius | Baseline | 197.2 mg/cm^3 | Standard Deviation 43.9 |
| Placebo | Trabecular Bone Mineral Density in the Ultradistal Radius | At 18 Weeks | 194.6 mg/cm^3 | Standard Deviation 41.2 |
| Placebo | Trabecular Bone Mineral Density in the Ultradistal Radius | At 36 Weeks | 213.1 mg/cm^3 | Standard Deviation 42.1 |
Secondary
Bone Strength Index, mg2/mm4
Measured at the 4% radius site.
Time frame: 36 weeks
Population: Sample size is smaller because scans with movement artifact were removed at baseline. At follow up, attrition also contributed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Calcium+VitD | Bone Strength Index, mg2/mm4 | Baseline | 19.8 mg^2/mm^4 | Standard Deviation 8.1 |
| Calcium+VitD | Bone Strength Index, mg2/mm4 | week 18 | 21.0 mg^2/mm^4 | Standard Deviation 9.1 |
| Calcium+VitD | Bone Strength Index, mg2/mm4 | week 36 | 23.1 mg^2/mm^4 | Standard Deviation 9.6 |
| Placebo | Bone Strength Index, mg2/mm4 | Baseline | 25.3 mg^2/mm^4 | Standard Deviation 15.9 |
| Placebo | Bone Strength Index, mg2/mm4 | week 18 | 22.9 mg^2/mm^4 | Standard Deviation 14.3 |
| Placebo | Bone Strength Index, mg2/mm4 | week 36 | 26.1 mg^2/mm^4 | Standard Deviation 14.5 |
Secondary
Cortical Bone Mineral Density
This was measured at the 20% radius site.
Time frame: 36 weeks
Population: Sample size reduced due to exclusion of scans with movement artifact and, in later visits, due to attrition as well.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Calcium+VitD | Cortical Bone Mineral Density | Baseline | 1059.6 mg/cm^3 | Standard Deviation 34.8 |
| Calcium+VitD | Cortical Bone Mineral Density | week 18 | 1062.8 mg/cm^3 | Standard Deviation 34.5 |
| Calcium+VitD | Cortical Bone Mineral Density | week 36 | 1069.3 mg/cm^3 | Standard Deviation 31.8 |
| Placebo | Cortical Bone Mineral Density | Baseline | 1063.2 mg/cm^3 | Standard Deviation 30.6 |
| Placebo | Cortical Bone Mineral Density | week 18 | 1060.2 mg/cm^3 | Standard Deviation 27.1 |
| Placebo | Cortical Bone Mineral Density | week 36 | 1058.7 mg/cm^3 | Standard Deviation 27.4 |
Secondary
Cortical Thickness
This was measured at the 20% radius site.
Time frame: 36 weeks
Population: Sample size reduced due to exclusion of scans with movement artifact and, in later visits, due to attrition as well.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Calcium+VitD | Cortical Thickness | Baseline | 2.25 mm | Standard Deviation 0.32 |
| Calcium+VitD | Cortical Thickness | week 18 | 2.25 mm | Standard Deviation 0.34 |
| Calcium+VitD | Cortical Thickness | week 36 | 2.32 mm | Standard Deviation 0.35 |
| Placebo | Cortical Thickness | Baseline | 2.34 mm | Standard Deviation 0.5 |
| Placebo | Cortical Thickness | week 18 | 2.26 mm | Standard Deviation 0.45 |
| Placebo | Cortical Thickness | week 36 | 2.34 mm | Standard Deviation 0.44 |
Secondary
Endosteal Circumference
This was measured at the 20% radius site.
Time frame: 36 weeks
Population: Sample size reduced due to exclusion of scans with movement artifact and, in later visits, due to attrition as well.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Calcium+VitD | Endosteal Circumference | Baseline | 16.0 mm | Standard Deviation 3.4 |
| Calcium+VitD | Endosteal Circumference | week 18 | 17.0 mm | Standard Deviation 3.9 |
| Calcium+VitD | Endosteal Circumference | week 36 | 16.8 mm | Standard Deviation 3.7 |
| Placebo | Endosteal Circumference | Baseline | 17.7 mm | Standard Deviation 3.6 |
| Placebo | Endosteal Circumference | week 18 | 18.4 mm | Standard Deviation 5.1 |
| Placebo | Endosteal Circumference | week 36 | 17.6 mm | Standard Deviation 4 |
Secondary
Periosteal Circumference
This was measured at the 20% radius site.
Time frame: 36 weeks
Population: Sample size reduced due to exclusion of scans with movement artifact and, in later visits, due to attrition as well.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Calcium+VitD | Periosteal Circumference | Baseline | 30.1 mm | Standard Deviation 4.3 |
| Calcium+VitD | Periosteal Circumference | week 18 | 31.2 mm | Standard Deviation 4.3 |
| Calcium+VitD | Periosteal Circumference | week 36 | 31.4 mm | Standard Deviation 4 |
| Placebo | Periosteal Circumference | Baseline | 32.4 mm | Standard Deviation 5.4 |
| Placebo | Periosteal Circumference | week 18 | 32.6 mm | Standard Deviation 6.1 |
| Placebo | Periosteal Circumference | week 36 | 32.3 mm | Standard Deviation 5.1 |
Secondary
Polar Section Modulus
This was measured at the 20% radius site.
Time frame: 36 weeks
Population: Sample size reduced due to exclusion of scans with movement artifact and, in later visits, due to attrition as well.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Calcium+VitD | Polar Section Modulus | Baseline | 123.8 mm^3 | Standard Deviation 53.6 |
| Calcium+VitD | Polar Section Modulus | week 18 | 134.5 mm^3 | Standard Deviation 55.1 |
| Calcium+VitD | Polar Section Modulus | week 36 | 137.2 mm^3 | Standard Deviation 49.2 |
| Placebo | Polar Section Modulus | Baseline | 156.2 mm^3 | Standard Deviation 76.6 |
| Placebo | Polar Section Modulus | week 18 | 156.8 mm^3 | Standard Deviation 91.9 |
| Placebo | Polar Section Modulus | week 36 | 151.9 mm^3 | Standard Deviation 75.6 |