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Vitamin D as a Therapeutic Adjunct in the Stimulant Treatment of ADHD

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ClinicalTrials.gov Identifier: NCT03103750
Recruitment Status : Recruiting
First Posted : April 6, 2017
Last Update Posted : January 9, 2019
Sponsor:
Collaborator:
Brain & Behavior Research Foundation
Information provided by (Responsible Party):
Yale University

Brief Summary:

Specific Aim 1: As part of a within-subject, two-days, study design, to determine whether acute calcitriol (vs. placebo) pre-treatment is associated with greater amphetamine (Amp)-induced dopamine (DA) release in the caudate, putamen, ventral striatum (VST), and substantia nigra / ventral tegmental area (SN/VTA) of healthy human subjects.

Specific Aim 2: To determine whether acute calcitriol (vs. placebo) pre-treatment is associated with better performance on a test of attention (e.g., the continuous Performance Task or CPT-AX), after treatment with amphetamine. Hypothesis: Investigators hypothesize that Subjects pre-treated with calcitriol will have faster reaction times/higher accuracy on the CPT-AX vs. subjects pre-treated with placebo, after treatment with amphetamine.


Condition or disease Intervention/treatment Phase
ADHD Procedure: Magnetic Resonance Imaging (MRI) Drug: Raclopride Dietary Supplement: calcitriol Drug: Placebo oral capsule Procedure: high-resolution research tomography Drug: Dextro Amphetamine Phase 1 Phase 2

Detailed Description:

Increases in the rates of childhood ADHD over the past two decades have lead to speculation that calcitriol deficiency (e.g., secondary to the increased use of sunscreen and/or increases in sedentary, indoor lifestyles in children) plays a causal/contributory role in the etiology of ADHD. To date, evidence of a direct link is lacking. One study showed higher maternal circulating Vitamin D levels in pregnancy are associated with lower risk of developing ADHD-like symptoms in childhood. On the other hand, another study did not replicate the above association, and a prospective study using umbilical cord samples stored at the time of birth reported no difference in serum vitamin D levels between ADHD group versus healthy controls. In terms of clinical trials, one randomized double blind study among adults with ADHD reported a beneficial effect of the intervention, measured with the Conners Adult ADHR rating scale, in comparison with placebo, but the intervention included the combination of vitamin D and several other micronutrients. An analysis of moderators of a positive response to ADHD behaviors did not reveal a significant predictive effect of vitamin D.

However, recent studies provide intriguing indirect evidence of an inverse relationship between solar intensity (SI) and/or altitude (a proxy for greater sun/UV light exposure) and regional rates of ADHD. One study examined three large datasets across 49 U.S. states for 2003 and 2007, and across 9 non-U.S. countries. This study examined the prevalence of ADHD and Solar Intensity (SI) maps. They found an inverse association between solar intensity and prevalence of ADHD. Another study examined two national survey datasets. They found an inverse relationship between altitude and prevalence of ADHD. Investigators hypothesize, as suggested by Huber, that a common denominator on the above studies is the increased vitamin D levels in those exposed to a higher solar intensity, which is known to increase with altitude.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: This is a within-subject, two-day four-scan, randomized, double-blind, placebo-controlled study design.
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Vitamin D as a Therapeutic Adjunct in the Stimulant Treatment of ADHD: a Proof-of-concept Study of Stimulant-induced Dopamine Release Using [11C]-Raclopride PET in Healthy Humans
Actual Study Start Date : August 15, 2017
Estimated Primary Completion Date : January 2022
Estimated Study Completion Date : January 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Vitamin D
Drug Information available for: Vitamin D

Arm Intervention/treatment
Experimental: Calcitriol then placebo
Healthy volunteers will receive a baseline MRI. On the night before, and day of testing subjects will receive two doses of calcitriol or placebo, followed by Raclopride injection & PET Scan #1. A minimum of six days later, subjects will receive a Dexedrine Dose followed by a second Racloporide injection and PET scan #2.
Procedure: Magnetic Resonance Imaging (MRI)
Magnetic resonance imaging (MRI) scans (3 T) will be collected in each subject for the purposes of excluding participants with anatomical abnormalities and anatomically co-registering PET and MRI for image analysis

Drug: Raclopride
Used as a tracer for in vivo imaging.

Dietary Supplement: calcitriol
three 0.5 mcg capsules

Drug: Placebo oral capsule
three 0.5 mcg capsules

Procedure: high-resolution research tomography
A functional imaging technique that is used to observe metabolic processes in the body.
Other Name: PET scan

Drug: Dextro Amphetamine
Dexedrine 0.3 mg/kg, to a maximum dose of 30 mg
Other Name: Dexedrine

Experimental: Placebo then Calcitriol
Healthy volunteers will receive a baseline MRI. On the night before, and day of testing subjects will receive two doses of calcitriol or placebo, followed by Raclopride injection & PET Scan #1. A minimum of six days later, subjects will receive a Dexedrine Dose followed by a second Racloporide injection and PET scan #2.
Procedure: Magnetic Resonance Imaging (MRI)
Magnetic resonance imaging (MRI) scans (3 T) will be collected in each subject for the purposes of excluding participants with anatomical abnormalities and anatomically co-registering PET and MRI for image analysis

Drug: Raclopride
Used as a tracer for in vivo imaging.

Dietary Supplement: calcitriol
three 0.5 mcg capsules

Drug: Placebo oral capsule
three 0.5 mcg capsules

Procedure: high-resolution research tomography
A functional imaging technique that is used to observe metabolic processes in the body.
Other Name: PET scan

Drug: Dextro Amphetamine
Dexedrine 0.3 mg/kg, to a maximum dose of 30 mg
Other Name: Dexedrine




Primary Outcome Measures :
  1. non-displaceable tracer binding potentials [ Time Frame: day 1 ]
    non-displaceable tracer binding potentials (BPND = VT - VREF / VREF), which are linearly proportional to the density of available D2/3 Rs, computed using a simplified reference tissue model (SRTM) utilizing the cerebellum as a reference region.

  2. non-displaceable tracer binding potentials [ Time Frame: day 7 ]
    non-displaceable tracer binding potentials (BPND = VT - VREF / VREF), which are linearly proportional to the density of available D2/3 Rs, computed using a simplified reference tissue model (SRTM) utilizing the cerebellum as a reference region.


Secondary Outcome Measures :
  1. continuous Performance Task (CPT-AX) [ Time Frame: day 1 ]
    In this computer based test the subjects are shown a random sequence of different letters and are instructed to press a button as quickly and accurately as possible (with their preferred hand) upon detection of an X after an A, and to withhold their response to any other sequence of letters.

  2. continuous Performance Task (CPT-AX) [ Time Frame: day 7 ]
    In this computer based test the subjects are shown a random sequence of different letters and are instructed to press a button as quickly and accurately as possible (with their preferred hand) upon detection of an X after an A, and to withhold their response to any other sequence of letters.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age 18-50 years
  • Voluntary, written, informed consent
  • Physically healthy by medical history, physical, neurological, ECG, and laboratory examinations
  • For females, non-lactating, with a negative serum or urine pregnancy test
  • Lab results without clinically relevant findings (e.g. renal function, electrolytes, and vitamin D levels)
  • English speaking

Exclusion Criteria:

  • Medical contraindication to Dexedrine administration (e.g., history of cardiac problems, seizures, glaucoma, hypertension, hyperthyroidism, etc.)
  • Medical contraindication to calcitriol administration (e.g., history of hypersensitivity to calcitriol or any component of the formulation, hypercalcemia or vitamin D toxicity)
  • History of substance dependence (e.g., alcohol, opiates, sedative hypnotics), except for nicotine
  • A primary major DSM-V psychiatric disorder (e.g., schizophrenia, bipolar disorder, major depression, etc.) as determined by the Structured Clinical Interview for DSM-V (SCID)
  • A history of significant medical (e.g., cardiovascular, diabetic/metabolic) or neurological (e.g., cerebrovascular accidents, seizure, traumatic brain injury) illness
  • Positive answers on the cardiac history questionnaire that may place the subject at higher risk, as determined by an internal medicine specialist or cardiologist's review of both the questionnaire responses and screening ECG
  • Current use of psychotropic and/or potentially psychoactive prescription medications
  • For females, laboratory (β-HCG) or physical evidence of pregnancy/lactation 9) MRI-incompatible implants and other contraindications for MRI (i.e., aneurysm clip, metal fragments, internal electrical devices such as a cochlear implant, spinal cord stimulator or pacemaker)
  • History of claustrophobia or feeling of inability to lie still on his/her back for the PET or MRI scans
  • History of any bleeding disorder or current anticoagulant therapy
  • Donation or loss of 550 mL of blood or more (including plasmapheresis) or receipt of a transfusion of any blood product within 8 weeks prior to the first test day.
  • Use of any prescription medications and/or over-the-counter medications, vitamins and/or herbal supplements which could have a negative clinical interaction with calcitriol/Dexedrine or which could confound scientific results of the study, within 2 weeks prior to each test day (e.g., thiazide diuretics, Mg based antiacids, digoxin, etc,.).
  • Serum levels of 25(OH)D3 below 20 ng/ml.
  • Obesity i.e. BMI over 30 (more prone to lower vitamin D levels)
  • Subjects with history of prior radiation exposure for research purposes within the past year such that participation in this study would place them over Radioactive Drug Research Committee (RDRC) limits for annual radiation exposure. This guideline is an effective dose of 5 rem received per year.
  • Subjects with current, past or anticipated exposure to radiation in the work place
  • History of kidney stones within the past 5 years
  • Any degree of renal failure
  • History of parathyroid disorder (hyper or hypoparathyroidism)
  • History of osteoporosis or any pathologic fractures
  • Vitamin D supplementation in any form in the past 3 months
  • Known hypersensitivity to Dexedrine, [11C] Raclopride, or calcitriol
  • Malabsorption syndromes (i.e. Celiac sprue)
  • Serum corrected calcium > 10.5 mg/dl or phosphate > 4.2 mg/dl

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03103750


Contacts
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Contact: Jessica Costeines, MSW 203-974-7559 Jessica.costeines@yale.edu

Locations
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United States, Connecticut
Connecticut Mental Health Center Recruiting
New Haven, Connecticut, United States, 06519
Contact: Jessica Costeines, MSW    203-974-7559    jessica.costeines@yale.edu   
Principal Investigator: Robert T Malison, MD         
Sponsors and Collaborators
Yale University
Brain & Behavior Research Foundation
Investigators
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Principal Investigator: Gustavo A Angarita, MD Yale University

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Responsible Party: Yale University
ClinicalTrials.gov Identifier: NCT03103750     History of Changes
Other Study ID Numbers: 1612018712
M# 25288 ( Other Grant/Funding Number: Brain and Behavior Research Foundation )
First Posted: April 6, 2017    Key Record Dates
Last Update Posted: January 9, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Yale University:
Vitamin D

Additional relevant MeSH terms:
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Amphetamine
Dextroamphetamine
Vitamins
Vitamin D
Ergocalciferols
Calcitriol
Central Nervous System Stimulants
Raclopride
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Bone Density Conservation Agents
Calcium-Regulating Hormones and Agents
Calcium Channel Agonists
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Vasoconstrictor Agents
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Dopamine Agents
Neurotransmitter Agents
Adrenergic Agents
Adrenergic Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Dopamine Uptake Inhibitors
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants