Citicoline, Creatine, and Omega-3 Effects in Middle Age Women
Phase: NA
Conditions: Cognitive Benefits
Sponsor: Deborah Yurgelun-Todd

 
Protocol Summary (ERICA) 
 
IRB_00048136 
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IRB Approval 8/31/2016 
 
 
Citicoline, Creatine, and Omega-3 Effects in Middle Age 
Women 
 
Protocol Summary 
 
 
 
IRB Approval Date of Current Version: 8/31/2016 
University of Utah IRB #: IRB_00048136 
Sponsor: UTAH SCIENCE TECHNOLOGY AND 
RESEARCH 
  
Principal Investigator: Deborah Yurgelun-Todd 
Internal Staff and  Sub-Investigators: 
Jennifer DiMuzio 
Melissa Lopez-Larson 
Erin McGlade 
Perry Renshaw 
 
External Sub-Investigators: 
 
 
 
This document was created using the ERICA Online System at the University of Utah. The document is created 
from study information approved by the IRB on the date listed above.  Any alteration to the original content of this 
document may not be considered to represent the study as approved by the IRB.  
 
 

 
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Background and Introduction 
 
Citicoline (CDP-choline; cytidine 5’-diphosphocholine) is a nucleotide that plays an 
important role in cellular metabolism. It has a number of putative mechanisms of action, 
including as a phospholipid precursor for neuronal membrane repair, for prevention of 
beta-amyloid deposition, and for promotion of neurotransmitter systems (Conant & 
Schauss, 2004).  Citicoline has been used therapeutically for stroke, traumatic brain 
injury, and cognitive dysfunction in the elderly (Adibhatla & Hatcher, 2005; Conant & 
Schauss, 2004) and it is available as a dietary supplement in the United States and Japan. 
Citicoline appears to work synergistically with omega-3 fatty acids (Carlezon et al., 2005), 
which must be incorporated into brain membranes in order to have antidepressant 
efficacy (Hirashima et al., 2004).  Omega-3 is also available as a dietary supplement in 
the United States.  It is high in EPA (eicosapentanoic), an active anti-inflammatory, and 
has been used by many to help stabilize mood and to support a healthy nervous system.  
In separate studies, the effects of creatine have also been evaluated (Lyoo et al., 2003; 
Allen et al., 2010).  Low doses of creatine, 4-5 grams/day appear to have marked 
antidepressant effects, especially in women (Lyoo and Renshaw, unpublished results; 
Kondo and Renshaw, unpublished results). 
References and Appendices: 
Adibhatla, R. M., & Hatcher, J. F. (2005). Cytidine 5'-diphosphocholine (CDP-
choline) in stroke and other CNS disorders. Neurochem Res, 30(1), 15-23. 
  
Allen PJ, D'Anci KE, Kanarek RB, Renshaw PF (2010). Chronic creatine supplementation 
alters 
            depression-like behavior in rodents in a sex-dependent manner. 
            Neuropsychopharmacology; 35(2):534-46. 
  
Carlezon WA Jr, Mague SD, Parow AM, Stoll AL, Cohen BM, Renshaw PF (2005). 
Antidepressant-like effects of uridine and omega-3 fatty acids are potentiated by 
combined treatment in rats. Biol Psychiatry, 57(4):343-50. 
  
Conant, R., & Schauss, A. G. (2004). Therapeutic applications of citicoline for 
stroke and cognitive dysfunction in the elderly: a review of the literature. Altern 
Med Rev, 9(1), 17-31. 
  

 
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Hirashima F, Parow AM, Stoll AL, Demopulos CM, Damico KE, Rohan ML, Eskesen JG, Zuo 
CS, Cohen BM, Renshaw PF (2004). Omega-3 fatty acid treatment and T(2) whole 
brain relaxation times in bipolar disorder. Am J Psychiatry 2004; 161(10):1922-4. 
  
Lyoo IK, Kong SW, Sung SM, Hirashima F, Parow A, Hennen J, Cohen BM, Renshaw PF 
            (2003). Multinuclear magnetic resonance spectroscopy of high-energy phosphate 
metabolites in human brain following oral supplementation of creatine-
monohydrate. Psychiatry Res; 123(2):87-100. 
  
Maher, B. A., Manschreck, T. C., Woods, B. T., Yurgelun-Todd, D. A., & Tsuang, M. 
T. (1995). Frontal brain volume and context effects in short-term recall in 
schizophrenia. Biol Psychiatry, 37(3), 144-150. 
  
Pope, H. G., Jr., & Yurgelun-Todd, D. (1996). The residual cognitive effects of 
heavy marijuana use in college students. JAMA, 275(7), 521-527. 
  
Yurgelun-Todd, D. A., & Kinney, D. K. (1993). Patterns of neuropsychological 
deficits that discriminate schizophrenic individuals from siblings and control 
subjects. J Neuropsychiatry Clin Neurosci, 5(3), 294-300. 
  
 
 
 
Purpose and Objectives 
 
We propose that nutritional supplements that combine citicoline, omega-3 fatty acids, and 
creatine are likely to have marked benefits, especially for female consumers.  We aim to 
determine the functional effects of citicoline, creatine and omega-3 fatty acids in 
combination when administered for a duration of four weeks (28 days) at a daily dosage 
to non-psychiatric adult female subjects.  The doses of 500 mg of citicoline, 5 grams of 
creatine, and 2 grams of omega-3 fatty acids have been selected from previous 
investigations and have demonstrated minimal side effects. 
 
 

 
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Study Population 
 
Age of Participants: 40-60 
 
Sample Size: 
At Utah: 
20  
All Centers: 
 
 
Inclusion Criteria: 
• Healthy female subjects, age 40-60 years 
  
• No significant medical condition 
  
• No history of co-morbid psychiatric disorder, current Axis I or II diagnosis or previous 
pharmacotherapeutic trial 
 
 
Exclusion Criteria: 
• Head injury w/ LOC > 5 minutes 
  
• Use of any psychotropic medication 
  
• History of a fish allergy 
  
• History of a medical condition that decreases coagulability 
  
• Use of anticoagulant medication 
 
 
 
Design  
 
Secondary/Archival Data Analysis 
Survey/Questionnaire Research 
Interviews and Focus Groups 
Prospective Clinical Research 
 
 
 
 
 
Study Procedures 
 
Recruitment/Participant Identification Process: 
Healthy, adult females will be recruited from the surrounding community through posting 
of flyers and word of mouth. All rules for posting flyers will be followed at every institution 
we canvass. Potential subjects will initially be screened over the phone by the study 
coordinator within a week of potential subjects calling the study voicemail number listed 
on the flyers.  The PI will review every phone screen to ensure that potential participants 
meet the most basic inclusion criteria for this study.  

 
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Informed Consent: 
Description of location(s) where consent will be obtained:  
Consent will be obtained in-person at the Brain Institute's clinical location at the 
University Neuropsychiatric Institute.  
 
Description of the consent process(es), including the timing of consent:  
Once the subject is deemed eligible for the study, consent will be obtained from the 
subject before any study-specific procedures are complete. During the consent process, 
participants will be able to take as long as they need to ask questions, read and sign the 
consent form. 
 
Procedures: 
The study is designed for a one-month completion.  Potential subjects will be screened in 
a 10-20 minute phone interview to determine eligibility.  The first visit will involve 
subjects reviewing and signing the consent form prior to engaging in any study 
procedures. All procedures listed are for research purposes only.            
Subjects will provide a urine sample for drug screening and a blood sample for serum 
glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase 
(SGPT).  A visual acuity test will be given as well as weight and height 
measurements.  The physical assessments will take approximately 30 minutes to 
complete.  Neuropsychological and clinical rating scales will be administered as well, 
taking approximately 1 hour and 30 minutes.  Each of the two visits should take 
approximately 2 hours to complete.  The subjects will then be given their complete supply 
of citicoline, creatine and omega-3 tablets and instructed to take a combined daily dose 
over the next 28 days.  They will be asked to return after 14 days for additional 
neuropsychological testing and clinical measures that will take approximately 1 
hour.  After 28 days, subjects will return for a repeat of measures for a second 2-hour 
evaluation session. 
Each participant will be given a supplement log at the end of visit 1.  They will be asked 
to complete the log during the 28 days to indicate that the daily dose of supplements 
were taken according to instructions.  The study coordinator will check the log on the 
second and third visits as well as count the remaining supplement pills.  If participants do 
not comply with the daily supplement schedule, then the PI will determine if the 
participant should be withdrawn from the study. 
Clinical Assessment 
The Mini International Neuropsychiatric Interview (M.I.N.I.) will be administered to each 
subject.  The M.I.N.I. is a diagnostic interview designed to assess basic functioning and 
symptoms for lifetime psychiatric disorders.  Subjects meeting diagnostic criteria for any 
psychiatric disorder, past or current Axis I or II, will not be included in the study.  The 
Positive and Negative Affect Scale (PANAS) will be given to each subject as a self-
evaluation scale in which subjects will rate their current feelings and emotions.  Mood and 
life style questionnaires will also be given to each subject.  The Columbia Suicide Severity 
Rating Scale (C-SSRS) will also be administered at each visit.  Finally, the Monitoring of 
Side Effects Scale (MOSES) will be given to study participants during the second and third 
visit to assess for any treatment side effects. If a subject becomes upset or 
uncomfortable during any part of the clinical assessment, they will be offered a chance to 

 
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take a break as well as other resources/referrals to help.  They will also be reminded 
about how their confidentiality and privacy are protected as well as the voluntary nature 
of the study.  The clinical assessment portion of the study should take approximately 30 
minutes. 
Neuropsychological Testing 
In addition to the clinical rating scales to be completed, the proposed investigation also 
includes a battery of neuropsychological tests designed primarily to evaluate general 
intellectual capacity, executive/attentional functions, and memory processing. A trained 
psychometrician will administer these measures.  All test scoring will be completed blind 
to subjects' treatment group status and clinical ratings. The neuropsychological tests were 
chosen because they are standard, well-known measures that can be administered and 
scored reliably.  Given the importance of accurately obtaining IQ estimates from subjects, 
we will administer four subtests from the WAIS III. These neurocognitive measures are 
well known to the principal investigator, and previous studies have demonstrated reliable 
performance (Maher, Manschreck, Woods, Yurgelun-Todd, & Tsuang, 1995; Pope & 
Yurgelun-Todd, 1996; Yurgelun-Todd & Kinney, 1993).  The measures include the 
following: Wechsler Adult Intelligence Scale (WAIS-IV): WAIS-IV Vocabulary Subtest, 
WAIS-IV Information Subtest, WAIS-IV Digit Span Subtests, WAIS-IV Block Design 
Subtest; WAIS-IV Coding Subtest; WAIS-IV Symbol Search Subtest; California Verbal 
Learning Test (CVLT)/ California Verbal Learning Test (CVLT-C); Rey-Osterreith Complex 
Figure Test (ROCFT); Continuous Performance Test (CPT); Stroop Color-Word Test; Trail 
Making Test; The Wisconsin Card Sort Test (WCST). 
WAIS-IV Vocabulary Subtest:  This subtest of the Wechsler Adult Intelligence Scale-
Revised measures the subject's verbal ability and has been shown to be highly correlated 
with measures of general intellectual ability. 
WAIS-IV Information Subtest: This subtest assesses the general knowledge of persons 
who grew up in the United States.  The items are arranged in order of difficulty, from the 
simplest to the most difficult, which few adults could answer. It measures verbal skills, 
breadth of knowledge, and remote memory.  It reflects formal education and a motivation 
for academic achievement.  Among brain injured populations, information tends to be one 
of the least affected measures and can therefore serve as an estimate of premorbid 
ability. 
WAIS-IV Digit Span Subtest: This subtest primarily measures the efficiency of attention. 
A subject repeats a string of digits presented by the experimenter.  In the first part the 
subject repeats the digits forward; on the second part the subject repeats the numbers in 
reverse sequence.  Failure on one of the two trials of this may be due to distraction, non-
cooperation, inattentiveness or lack of concentration.  Repetition backwards uses 
"working memory" and involves mental double-tracking in that both the recall of the 
number sequence and the reversing operations must proceed simultaneously. 
WAIS-IV Block Design Subtest:  This test of visuoconstructional ability is recognized as a 
test of visuospatial planning and function.  It has been shown to be correlated with 
measures of general intellectual ability.  In this test, the subject is presented with 
identical red and white blocks and asked to construct 8 designs presented to him on a 
stimulus card. The blocks are made up of distinguishable faces, 2 red sides, 2 white sides, 

 
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and 2 red & white sides split diagonally. Concrete minded persons have particular 
difficulty constructing the designs with diagonal patterns. 
WAIS-IV Coding Subtest:  This subtest assesses visual-motor coordination, motor and 
mental speed. 
WAIS-IV Block Symbol Search Subtest:  A series of paired groups, each pair consisting of 
a target group and a search group. The examinee indicates, by marking the appropriate 
box, whether either target symbol appears in the search group. 
California Verbal Learning Test (CVLT): This verbal learning test assesses the subject's 
immediate and delayed recall, as well as suggesting the strategy utilized for retrieval of 
newly-learned information.  Subjects are asked to remember a 16-item word list, which is 
presented on five trials.  After each trial, the subject is asked to recall all of the words 
that they can remember.  A second list is then presented to provide an interference 
condition.  The subject is then asked to recall the first word list.  After a temporal delay, 
the subject is again asked to recall the first word list.  Test results provide scores for 
assessing verbal learning, strength of memory following interfering tasks, proactive 
interference, accuracy of recognition memory and storage versus retrieval of newly 
learned information. 
Continuous Performance Test (CPT): This classic test of sustained attention has been 
adapted to a computerized version that can be administered to study subjects in 14 
minutes.  A subject is required to attend vigilantly to a series of visual stimuli and to 
indicate when target stimuli appear, disregarding distracter stimuli in which the target 
stimuli are embedded.  This task generates measures of reaction time, omission errors, 
and commission errors, as well as an index of overall performance.  Poor performance on 
the CPT has been associated with a number of psychiatric disorders. Scores include 
reaction time, omission errors, and commission errors, as well as an index of overall 
performance. 
Rey-Osterreith Complex Figure Test: This complex figure test is an assessment of visuo-
organizational ability, visual attention, and visual memory.  The subject is asked to copy a 
complex figure, which is then evaluated for strategy, constructional accuracy, and detail 
reproduction.  After removing the stimulus and the copy, the subject is asked to 
reproduce what he can recall from the figure.  Approximately 30 minutes later, he is 
asked again to reproduce the figure.  The complex design can be scored in both recall 
conditions on the basis of the number of elements, which have been correctly 
recalled.  The difference between immediate and delayed performance scores is a 
measure of temporary decay for visuospatial memory. 
Stroop Color-Word Test:  This test measures the ability to inhibit inappropriate responses 
and resist interference.  This test procedure includes three sections (color naming, word 
reading and interference) and is designed to establish competing response tendencies 
within the study subject and to assess the ability to suppress the interfering stimuli. 
Dependent measures include both reaction time to complete each condition, as well as 
total errors of omission and commission per condition. Difficulty with inhibition is reflected 
by an increase in errors and/or time in the interference section relative to the color 
naming or word reading sections. 
Trail Making Test: This test is designed to measure visual conceptual and visuomotor 
tracking, as well as maintenance of cognitive set. The subject must first draw lines to 

 
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connect consecutively numbered circles on one work sheet (Part A) and then connect the 
same number of consecutively numbered and lettered circles on another work sheet by 
alternating between the two sequences (Part B). Trails B is the more sensitive of the two 
tests -- particularly to frontal-lobe dysfunction -- as scores on this section are indicative 
of the subject's ability to shift sets and process concurrent stimuli. 
The Wisconsin Card Sort Test: The Wisconsin Card Sort Test (WCST): This test assess a 
person's ability to form abstract concepts, utilize feedback, and to shift and maintain set, 
and has been used extensively in the evaluation of patients with frontal lobe damage, as 
it has been shown to be sensitive to frontal dysfunction. The test consists of 4 stimulus 
cards, varying in color, geometric form, and number.  Without a time limit, the subject 
has to match each of the cards in the deck to a key card. No explanation is given to the 
subject as to the criterion being used in making a match.  For each attempt, the subject 
is told if the trial is a correct or incorrect match.  After each sequence of ten correct 
responses, the tester changes the match criterion without giving warning to the subject. 
Total number of categories correct, perseverative and other error types are dependent 
variables. 
  
 
 
Procedures performed for research purposes only:  
 
 
 
Statistical Methods, Data Analysis and Interpretation 
 
This study is designed to explore whether oral supplementation of citicoline, creatine, and 
omega-3 fatty acids in combination for one month will result in cognitive improvements 
that correlate with brain activation and metabolism changes in 20 healthy adult females, 
ages 40-60.  Data will be expressed as mean ± standard deviation, except where noted. 
Variables will be compared using ANOVAs with a=.05. All statistics will be computed using 
SPSS version 11.0 for the Macintosh.  We will also examine the association between 
neuropsychological measures of attention, cognitive inhibition and memory as well as 
clinical measures for mood.