Clinical trial NCT02134808
Conditions: Major Depressive Disorder
Keywords: Major Depressive Disorder Creatine Brain Chemistry Magnetic Resonance Spectroscopy Treatment Resistance Selective Serotonin Reuptake Inhibitor (SSRI) Resistance
Sponsor: Perry Renshaw
Start date: 2014-11-21; Completion date: 2017-06-27
Enrollment: 71 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary hypothesis is that compared to placebo, 10g of daily creatine monohydrate for eight weeks will be associated with significant increases in frontal lobe phosphocreatine and beta-nucleoside triphosphate (β-NTP) concentrations. A secondary hypothesis is that decreased depressive symptoms measured with the Children's Depression Rating Scale-Revised (CDRS-R) and Montgomery-Asberg Depression Rating Scale (MADRS) will be reciprocally correlated with increased β-NTP concentrations.

Detailed description:
The current protocol seeks to expand upon the investigators previous work by opening recruitment on a pilot study of creatine 10g daily vs. placebo as a treatment for female adolescents with SSRI-resistant MDD. The purpose of the pilot study is twofold: A) to evaluate several aspects of the feasibility of creatine supplementation as a treatment for this population; and B) to estimate the effect size of adjunctive creatine, to inform the design and implementation of a potential future efficacy trial.

Arms: arm 1: Subjects randomized to this study arm will receive 10 grams of creatine daily for 8 weeks. arm 2: Subjects randomized to this study arm will receive 10 grams of placebo daily for 8 weeks.
Interventions: intervention 1: Creatine intervention 2: Placebo
Intervention descriptions: intervention 1: Creatine is a nutritional supplement. intervention 2: The placebo is an inactive ingredient similar in appearance, weight and density to the active treatment.

Protocol documents:
Prot_SAP_000.pdf: 
STUDY PROTOCOL 
PROTOCOL TITLE: Placebo-Controlled Trial of Creatine Augmentation 
for Adolescent Females with Treatment-Resistant 
Major Depressive Disorder: a Magnetic Resonance 
Spectroscopy Study 
PROTOCOL DATE: 06/17/2015 
             NCT NUMBER: NCT02134808 
PRINCIPAL INVESTIGATOR: Perry Renshaw, MD, PhD, MBA 
Professor of Psychiatry 
The Brain Institute | University of Utah 
383 Colorow Drive 
Salt Lake City, UT 84108 
CO-INVESTIGATORS: Douglas Kondo, MD 
Assistant Professor of Psychiatry 
The Brain Institute | University of Utah 
383 Colorow Drive 
Salt Lake City, UT 84108 
Younghoon Sung, MD, MS 
Assistant Professor of Psychiatry 
The Brain Institute | University of Utah 
383 Colorow Drive 
Salt Lake City, UT 84108 
Xianfeng Shi, PhD 
Research Instructor of Psychiatry 
The Brain Institute | University of Utah 
383 Colorow Drive 
Salt Lake City, UT 84108 


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BACKGROUND AND INTRODUCTION:  
 
Pediatric Depression: Epidemiology and Limitations of Current Drug Treatments 
Pediatric major depressive disorder (MDD) is an important public health problem.  With 
an annual incidence of about 2% in children and 4% to 8% in adolescents [1], and a cumulative 
lifetime prevalence of up to 20% [2], MDD in young people is associated with academic and 
social impairment, substance abuse, and suicide attempts [1].  Compared with healthy controls, 
depressed adults are more likely to have had a depressive episode in adolescence [3].  Kandel 
and colleagues [4] conducted a long-term study of 1,004 public high school students in the state 
of New York, and their study findings noted that depressive feelings in adolescence were likely 
to persist into adulthood, and to predict psychiatric hospitalization for women (but not men).  In 
addition, adolescent depression was associated with a number of poor outcomes in adulthood:  
cigarette smoking, increased use of prescription tranquilizers in females, socially deviant 
activities and accidental injury [4].  Adding to the morbidity and mortality experienced by 
adolescent patients and their families, pediatric depression imposes a substantial economic 
burden on society [5].  Therefore, the discovery of novel effective treatments for patients with 
depression in the critical adolescent stage of development has immense public health 
implications [6-9]. 
In the United States (U.S.), selective serotonin reuptake inhibitors (SSRIs) have been 
the predominant method for treatment of adolescent depression for more than a decade [10].  
Drug treatment of depression in youth has become standard practice, in part because of the 
failure of most evidence-based psychotherapy treatments to make their way into everyday 
practice [11].  Despite the increased attention to pediatric MDD sparked by the U.S. Food and 
Drug Administration’s (FDA’s) “Black Box” warning applied to antidepressants prescribed to 
children and adolescents [12], the pharmacological treatment options remain limited.  In a 
systematic review of 13 randomized placebo-controlled trials for pediatric depression involving 
2,750 participants, Usala and colleagues found a pooled response rate of 59.5% (95% C.I. 
57.2–62.5) and a placebo response rate of 47.9% (95% CI, 45.5–51.1) [13].  Combined risk 
differences in rates of antidepressant response status favored antidepressants over placebo by 
just 11.0 % (95% C.I. 7.1–14.9).  Similarly, a recent study that specifically examined the placebo 
response in pediatric MDD trials found that the mean proportion of participants per study 
responding to placebo was 0.46 (S.D.=0.08; Range=0.33–0.57) [14]. 
The number needed to treat [15] (NNT) is an evidence-based medicine statistic that 
represents the relative benefit of treatment compared with the control condition.  The NNT is the 
number of patients a clinician must treat to prevent one adverse outcome (e.g. unremitted 
depression in one patient).  Tsapakis and colleagues conducted a meta-analysis of 30 
randomized, placebo-controlled trials for pediatric depression.  The NNT for antidepressants in 
pediatric MDD is 9.35 (95% C.I. 7.1-13.7) [16].  As a measure of treatment effect, the practical 
implication is that a practicing clinician must treat nine patients with antidepressants in order for 
one pediatric patient with MDD to recover who would otherwise not have.  Meanwhile, the 
clinician must expose all nine patients to an approximate doubling of the risk for suicidal ideation 
or behavior [17].  With greater than 40% of pediatric MDD patients classified as antidepressant 
non-responders and a narrow therapeutic margin between antidepressants and placebo, new 
treatment options are urgently needed.   
The selective serotonin reuptake inhibitor (SSRI) antidepressants, including fluoxetine 
(Prozac®) have become the treatment of first choice in pediatric MDD, owing to the results of 
the NIH-sponsored Treatment for Adolescents with Depression Study (TADS) clinical trial [18]. 
The U.S. FDA and the U.K. Medicine and Health Care Products Regulatory Agency have 
concluded that an acceptable risk/benefit relationship exists for fluoxetine in pediatric MDD [19].   
The European Medicines Agency initially concluded that fluoxetine should not be prescribed to 
minors, but later adopted a positive opinion for the use of Prozac® in children 8 years and older 


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with depression [20].  Fluoxetine is a recommended treatment for pediatric MDD in the Texas 
Children's Medication Algorithm Project [21]. In March 2009, the FDA approved the use of the 
SSRI escitalopram (Lexapro®) for acute and maintenance treatment of adolescent MDD. The 
approval was supported by two placebo-controlled studies.  Emslie et al. [22] conducted a large 
randomized control trial evaluating the efficacy and tolerability of escitalopram in treating 
adolescent MDD. Significant improvements in Children’s Depression Rating Scale-Revised 
(CDRS-R) scores from baseline to the end of treatment were found in the escitalopram group. 
These findings were consistent with a similar trial conducted by Wagner, et al. [23].  In addition 
to fluoxetine and escitalopram, the SSRI medications commonly used in the U.S. to treat 
adolescent depression include citalopram (Celexa®), sertraline (Zoloft®) and paroxetine 
(Paxil®).  The NIH-sponsored $17 million TORDIA (Treatment Of Resistant Depression In 
Adolescents) multi-center clinical trial [125] established the accepted definition, in terms of 
medication dosages and durations, of treatment-resistant adolescent MDD. 
 
Females Have an Increased Rate of Depression in Adolescence 
Early-onset psychiatric disorders (e.g., conduct problems, autism, ADHD) show a 
marked male preponderance, whereas adolescent-onset disorders (e.g., depression, anxiety) 
show a marked female preponderance [24].  The prevalence of depression increases several 
fold following puberty, from 1% in childhood to 8% in adolescence [25].  The cumulative lifetime 
prevalence for depressive disorders in adolescence is estimated at 15-20%, which is 
comparable to the rate found in the adult population [25].  A number of epidemiologic studies 
have shown that the illness burden is borne primarily by female adolescents [26-29]. 
Evidence supports puberty as the transitional period in which the risk for depression 
rises in female adolescents.  The age at menarche was found to be the transition point in one 
study [30].  Similarly, the elevated rate of depressive symptoms and major depressive disorder 
in females emerged once participants had reached Tanner Stage III [31] in the Great Smoky 
Mountain Study (GSMS) [32].  Further analyses of the GSMS participants’ hormonal status was 
performed, revealing that changes in gonadal steroids were closely correlated with the rise in 
depressive symptoms [33].  Statistical models incorporating testosterone and 17β-estradiol 
levels eliminated the apparent effect of Tanner stage (physical development), leading the 
investigators to conclude that research on increased depression in females needs to focus on 
factors associated with changes in androgen and estrogen levels [33].  Available data suggest 
that estrogen, or its absence, is strongly implicated in the regulation of mood and behavior, as 
well as in the neurobiology of mood disorders [34].  The multiple effects of estrogens and their 
complex interactions with the brain and endocrine system have been well-documented, 
although the specific role of estrogen in depression has yet to be elucidated [34]. 
 
By the middle teenage years, females experience more than double the rate of 
depressive disorders found in males [26, 29].  This approximate 2:1 gender difference in 
depression continues throughout the reproductive years [35].  In addition to the increased 
incidence, initial episodes of depression are longer in duration and more severe in 
symptomatology in girls compared to boys [36].  Girls with MDD have a prolonged period of risk 
for recurrent depression, compared with women who have their first depressive episode as an 
adult [37, 38].  Women are more likely than men to have atypical symptoms of depression (e.g. 
hypersomnia, hyperphagia), to have co-morbid anxiety disorders, and to attempt suicide; 
Seasonal Affective Disorder is also more common in women [39].  In a global sense, depression 
is among the most common disorders affecting females throughout their lives, and is the 
leading cause of disability among women between the ages of 15 and 44 [40]. 
 
Metabolic Changes Associated with Depression:  Findings from Magnetic Resonance 
Spectroscopy Brain Imaging Studies 


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To shed light on the neurobiology of depressive disorders requires the establishment of 
measurable correlates of illness and recovery.  Converging lines of evidence suggest that mood 
disorders are associated with changes in brain energy metabolism [41-44], which normalize with 
resolution of a mood episode [45, 46].  These changes in brain energy metabolism can be 
measured with a non-invasive neuroimaging technique which uses no radiation:  phosphorus-31 
magnetic resonance spectroscopy (31P-MRS) [47].  At magnetic field strengths of 1.5 Tesla or 
higher, proton magnetic resonance spectroscopy (1H-MRS) allows the ascertainment of values 
of myo-inositol, choline-containing compounds, creatine, glutamate, glutamine, and N-acetyl 
aspartate [48].  At similar field strengths, cerebral 31P-MRS can measure levels of 
phosphomonoesters, inorganic phosphate, phosphodiesters, phosphocreatine (PCr), and the 
gamma, alpha and beta nucleotide triphosphate (mainly adenosine triphosphate (ATP)) 
resonances [48].  PCr represents a high-energy reservoir linked to ATP in a bidirectional pH-
dependent chemical reaction in which ATP is formed by PCr and vice versa with a 1:1 
(PCr:ATP) molar ratio [49].  The equilibrium for this reaction favors ATP formation so that 
energy demands in excess of the cellular capacity for ATP synthesis are met initially through a 
shift in this equilibrium, which maintains ATP concentration constant through PCr hydrolysis 
[50].  Previous 31P-MRS studies support a model of mitochondrial dysfunction in MDD involving 
impaired oxidative phosphorylation and a shift toward glycolysis, which results in decreased 
regional brain pH [51]. 
In 1992, Kato et al. were the first to report 31P-MRS findings in MDD [52].  The 
investigators measured brain phosphorus metabolism in 22 patients with depressive disorders.  
PCr (a high-energy phosphate storage compound) was significantly decreased in severely 
depressed patients compared to patients with mild depression. Moore and colleagues [53] noted 
that beta nucleoside triphosphate (β-NTP) resonance, which arises primarily from ATP, was 
16% lower in adults with major depressive disorder (MDD) than in healthy controls.  Similarly, in 
a study evaluating abnormalities in cerebral purine metabolism in MDD, researchers found that 
baseline β-NTP was lower, by 21%, in adult females with MDD who responded to SSRI 
treatment relative to non-SSRI responders [47].  Forester and colleagues [54] detected reduced 
β-NTP and total NTP in depressed geriatric subjects relative to a comparison group.  Finally, 
Kondo et al. [55] found lower PCr/β-NTP levels in depressed female adolescents compared to 
healthy controls.  These findings suggest that high-energy phosphate metabolism, intracellular 
pH and membrane phospholipid metabolism may be altered in depression [52].   
31P-MRS findings in adults with MDD have consistently shown a characteristic pattern of 
metabolic change:  reduced β-NTP and increased PCr [46, 53, 56].  This pattern, which is more 
common in females than males [47], suggests that some depressed patients have increased 
brain energy stores they cannot access to support cerebral activity.  This specific pattern of 
altered energy metabolism is associated with an increased likelihood of treatment response to 
both SSRI antidepressants and thyroid hormone [46].  In healthy adults, administration of the 
dietary supplement creatine can induce the equivalent changes in resting brain chemistry [57], 
suggesting the possibility of using creatine supplementation to modify brain high-energy 
phosphate metabolism in patients with depression.   
 
Creatine Supplementation 
A French scientist, Michel Eugene Chevreul, first described creatine as a nitrogenous 
organic acid that occurs naturally in vertebrate animals in the 1830s.  The capacity for creatine 
biosynthesis via the creatine-kinase-phosphocreatine energy buffering system was established 
early in the history of life on Earth [58].  Acting as a substrate for hydrogen ions, creatine 
facilitates the production of adenosine triphosphate (ATP) from adenosine diphosphate (ADP), 
thus increasing the amount of free energy available within cells [59].  


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Creatine has a role in high-energy phosphoryl group transfer during skeletal muscle 
contraction via the creatine kinase reaction.  The enzyme creatine kinase catalyzes the 
reversible reaction of creatine and ATP, forming PCr and ADP [60].  The intracellular 
creatine/PCr ratio plays an important role in maintaining an adequate supply of energy, in the 
form of cellular ATP [61].  PCr may be viewed as a reservoir of “high-energy phosphate,” which 
is able to supply to ATP, the primary energy source in cells, on demand.  Consequently, 
creatine plays a significant role in energy homeostasis of cells with intermittently high energy 
requirements [60].  In humans, brain and muscle are two such tissue types. 
Creatine plays a role in transferring energy from the mitochondria to the cytosol in 
tissues with high energy requirement such as brain and skeletal muscle [62].  Creatine was also 
recently identified as a potent natural survival- and neuroprotective-factor for developing nigral 
dopaminergic neurons [63].  Creatine supplementation improves the function of creatine 
kinase/PCr system by increasing cellular creatine and PCr levels, improving the rate of ATP re-
synthesis, and maintaining cellular-energy homeostasis [64].   
Clinical trials in humans provide evidence for creatine's effect on brain function.  A study 
published by Rae et al. [65] showed that increasing oral creatine intake resulted in a significant 
positive effect on both working memory and intelligence.  These results were in agreement with 
the observations that brain creatine levels correlate positively with recognition memory [66], and 
that creatine supplementation reduces mental fatigue on a serial calculation task [67].  The latter 
study also showed reduced activation-stimulated oxyhemoglobin delivery to the activated area 
following creatine supplementation [67].  This suggests that creatine supplementation is acting 
to smooth fluctuations in the blood oxygen level-dependent response curve, which results from 
brain activation [68, 69], possibly by altering rates of ATP synthesis in the mitochondrion 
through the mitochondrial creatine kinase-adenine nucleotide translocase-porin complex [61, 
70].  Lyoo and colleagues [57] administered oral creatine to a sample of healthy volunteers, and 
the results of their study indicated that PCr concentrations increased over time in the creatine 
group relative to the placebo group.  
Creatine is currently being investigated as a treatment for neuromuscular and 
neurodegenerative diseases.  Walter et al. [71] administered creatine to treat Muscular 
Dystrophy in a double-blind placebo-controlled trial.  The study enrolled 32 participants and 5 
grams/day of creatine was administered [71].  The researchers noted a significant improvement 
in muscle strength and daily activities in the creatine group and there were no reported side 
effects from creatine use [71].   
Creatine supplementation has also been used for the treatment of Huntington’s Disease 
(HD).  Study findings suggest that PCr and inorganic phosphate are reduced in the cortex and 
basal ganglia of HD patients [72].  Creatine supplementation in animal models of HD has been 
shown to reduce neuronal atrophy, extend survival, attenuate the loss in brain weight, lower the 
number of Huntington-positive aggregates, and improve motor performance [73-75].  Moreover, 
creatine supplementation has been shown to be neuroprotective, and to reduce lesion volume in 
mitochondrial toxin models of HD [76].  Hersch and colleagues [77] conducted a double-blind 
placebo-controlled trial testing the safety and tolerability of creatine administration in HD 
patients.  In addition, they evaluated brain and serum biomarkers of creatine availability and 
activity [77].  Participants took 8 grams of creatine daily for 16 weeks, which was well tolerated 
with no treatment-emergent safety issues [77].  The researchers noted increased brain and 
serum creatine concentrations in the creatine-treated group, which returned to baseline after a 
washout period [77].   
There is strong evidence that altered energy metabolism due to mitochondrial dysfunction plays 
a role in the pathogenesis of Parkinson’s Disease (PD) [78].  Due to this bioenergetic 
impairment, creatine has been explored as a PD treatment option.  Matthews et al. [76] noted 
that oral creatine supplementation resulted in protection against an electron transport chain of 
mitochondria called 3-nitropropionic acid, 1-methyl-4-phenyl-2,3,6-tetrahydropyridine (MPTP)-


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induced dopamine depletion in mice.  In a randomized double-blind clinical trial of creatine in 
early PD patients, creatine supplementation delayed increases in the Unifed Parkinson’s 
Disease Scale by as much as 50% [79].  Creatine is currently under investigation in a Phase III 
trial examining 1,720 patients with PD (http://clinicaltrials.gov/ct2/show/NCT00449865). 
 
 
Creatine has Potential Antidepressant Effects in Females 
Data from preclinical animal studies suggest that creatine has sex-dependent 
antidepressant properties.  The Porsolt Forced Swim Test (FST) is the most widely employed 
experimental animal model of depression.  Fed to rats, diets enriched with 4% creatine for six 
weeks confer a longer latency to immobility in female rats compared with rats fed 0% creatine.  
In male rats, however, creatine has the opposite effect [80].  Moreover, supplementation with 
4% creatine in female rats was of greater benefit for reducing depression-like behavior than 
10mg/kg of fluoxetine (Allen, 2011, unpublished findings).  The gender-specific nature of these 
findings may be due to the fact that estrogen receptors are quite common on mitochondria [47].  
Estrogen has potent effects on mitochondria, particularly in times of mitochondrial stress [81].  
Estrogen has cell-specific effects on a variety of physiologic endpoints, including regulation of 
mitochondrial biogenesis and activity [82].   
In terms of data from human subjects trials, here at the University of Utah, we have 
completed two studies of creatine augmentation in female adolescents with SSRI-resistant 
major depression.  The first study was an eight-week open label study, which was conducted 
under U.S. Food and Drug Administration (FDA) Investigational New Drug Application (IND) 
#104,586. The second study was a placebo-controlled dose-ranging trial conducted under the 
same IND, which sought to determine which of four daily doses of adjunctive creatine 
(0g/placebo, 2g, 4g, or 10g), when added to participants’ current antidepressant treatment, 
offers the best combination of efficacy, tolerability and safety.  The National Institute of Mental 
health (NIMH) funded the dose-ranging trial as an R21 study, and contingently awarded funds 
for a 3-year R33 study based on the R21’s success. 
In the open-label study, participants' Children's Depression Rating Scale (CDRS-R) 
scores were reduced by 44% [55].  Moreover, utilizing pre- and post-treatment brain scans we 
found that brain PCr concentrations increased with eight weeks of creatine supplementation 
when compared to a comparison group of non-depressed adolescent controls [55].  In the dose-
ranging study, participants were randomly assigned to treatment from one of the four study drug 
groups for 8 weeks.  Participants randomized to all creatine treatment groups showed greater 
decreases in CDRS-R scores, with reductions between 28-42%, compared to the CDRS-R 
scores of participants randomized to placebo, who showed a decrease of 24% [unpublished 
data]. Participants treated with 10g daily creatine showed the highest increases in frontal lobe 
PCr, and were the only participants showing post-treatment increases in frontal lobe beta-NTP.  
In both studies, creatine was well-tolerated, and participants experienced no suicide attempts or 
psychiatric hospitalizations over the 8-week trial.  We observed no persistent or clinically 
significant abnormalities on serum or urine laboratory tests.  
The neuroimaging and clinical results from the R21 study suggest that daily adjunctive 
treatment of 10g creatine is associated with the greatest change in PCr, and higher PCr is 
associated with lower depression scores.  Therefore, the dose of creatine our data suggests is 
most likely to engage the neurochemical target is the 10g dose.  At the same time, our data do 
not suggest that the 10g dose poses significantly greater risks to subjects compared with 
placebo, other than weight gain attributable to intracellular water. 
The current protocol seeks to expand upon our previous work by opening recruitment on 
a pilot study of creatine 10g daily vs. placebo as a treatment for female adolescents with SSRI-
resistant MDD.  The purpose of the pilot study is twofold: A) to evaluate several aspects of the 
feasibility of creatine supplementation as a treatment for this population; and B) to estimate the 


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effect size of adjunctive creatine, to inform the design and implementation of a potential future 
efficacy trial. 
In addition, a large-scale trial of SSRI+Creatine vs. SSRI+Placebo for adult females with 
MDD was recently completed. (See: http://clinicaltrials.gov/ct2/show/NCT00729755)  The daily dose 
of creatine was 5 gm.  The data suggest that adjunctive creatine was safe and well-tolerated, 
and that the creatine experienced an earlier response and an increased likelihood of achieving 
remission. 
 
Safety Profile and Toxicity of Creatine in Adults 
The Cochrane Database of Systematic Reviews is the gold standard for evidence-based 
medicine meta-analyses.  In 2007, Kley and colleagues published a review on behalf of the 
Cochrane Collaboration that pooled results of 12 randomized controlled trials (RCTs) of creatine 
which enrolled 266 patients with muscle disorders [83].  The authors concluded that there were 
no significant side effects associated with creatine at recommended doses.  High-dose creatine 
(150mg/kg/day, or 6.8 grams per day for a participant weighing 100 lbs., 13.6 grams per day for 
a participant weighing 200 lbs.) increased patients’ muscle pain when it was used to treat 
Glycogen Storage Disease Type V.  The same authors published a summary of their findings in 
the Journal of Neurology, Neurosurgery and Psychiatry [84], stating that:  “No trial reported any 
clinically relevant adverse event.” 
Prospective and retrospective studies in humans have found no evidence for long-term 
or short-term significant side effects from creatine supplementation taken at recommended 
doses [85-88].  Most controlled studies of creatine report an absence of side effects or report no 
difference in the incidence of side effects between creatine and placebo [89].  Mihic and 
colleagues have demonstrated that creatine loading increases fat-free mass, but does not affect 
blood pressure, plasma creatinine, or creatine kinase activity in adult men and women [88]. 
Reports in the popular media of links between creatine use and muscle strains, muscle 
cramps, heat intolerance, and other side effects are not supported by the medical literature [89]. 
Studies conducted in athletes and military personnel indicate a substantial level safety of both 
short- and long-term creatine supplementation in healthy adults [86, 90-94].  Concerns about 
high-dose creatine’s association with renal toxicity are based exclusively on two published case 
reports; in one of the cases the patient had a documented pre-existing kidney condition [95, 96].  
Literature reviews and expert consensus panels have concluded there is no evidence 
supporting an association between creatine and renal disease [86, 97-100]. 
Concern has been raised regarding creatine’s potential for adverse effects on the 
kidneys and renal system, in part because creatine supplementation can increase urinary 
creatine and creatinine excretion [101].  In response to the concerns regarding creatine and 
renal toxicity, Poortmans conducted studies of the effect of creatine supplementation on renal 
function, showing that short-term supplementation does not alter glomerular filtration rate [85], 
and that chronic supplementation of up to five years’ duration did not impair renal function in 
healthy athletes [86].  In a letter published in The Lancet, Poortmans reported that his 
laboratory’s results show that oral creatine supplementation has no adverse effects on the renal 
responses of healthy individuals [102]. 
Gualano et al. conducted a randomized, double-blind, placebo-controlled trial of the 
renal effects of high-dose (10 grams/day) creatine supplementation for 3 months [103].  The 
outcome measures included serum creatinine, serum and urinary sodium and potassium at 
baseline and at the end of the study.  The authors concluded that high-dose creatine 
supplementation daily for 90 days does not provoke renal dysfunction [103]. 
In 2010, to address concerns about creatine and renal toxicity, the prestigious British 
Medical Journal published a “Lesson of the Week” demonstrating how -- and why -- non-
nephrologists misdiagnose kidney disease in patients taking creatine [104]. Previously, it 
was also suggested that oral creatine had the potential to give rise to carcinogen formation 


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[105], due to the low pH and presence of nitrite in the human digestive tract – conditions which 
could theoretically result in formation of N-nitrososarcosine (NSAR) [106].  To address this 
concern, Derave and colleagues conducted a placebo-controlled trial of daily creatine at both 
high (20 grams/day) and low (5 grams/day) doses [107].  The average age of participants was 
18.8 years, and the study lasted 20 weeks.  Systemic NSAR was measured acutely and after 20 
weeks, and the investigators found no difference in NSAR in the creatine group compared with 
the placebo group [107].  The study found that that creatine supplementation does not result in 
the formation of NSAR in the human gastrointestinal tract, as had been previously hypothesized 
(but not verified via the scientific method).  The authors concluded that there is no evidence that 
creatine is carcinogenic through formation of NSAR [107]. 
Another hypothesis regarding creatine’s potential for adverse effects was put forth by 
Yu, who posited that because creatine can be metabolized to methylamine, the downstream 
effect of creatine supplementation might be increased formaldehyde [108], which is a known 
human carcinogen.  Other health factors believed to increase levels of formaldehyde include 
exposure to nicotine [109], and elevated levels of stress-related adrenaline [110]. 
To examine the creatine-formaldehyde hypothesis, Candow and colleagues 
administered creatine at a dose of 8 grams/day together with a protein supplement to elderly 
men aged between 59 and 77 years [111].  Urine specimens were collected before-and-after 
creatine supplementation, and formaldehyde levels were measured.  The authors concluded 
that creatine supplementation in elderly men reduces muscle breakdown and bone resorption, 
but does not result in an increase in systemic formaldehyde [111]. 
Schilling and colleagues conducted a retrospective study of participants who had been 
taking oral creatine from 0.8 to 4 years, at an average dose of 9.7 grams per day [112].  Data 
was collected on 65 health-related variables.  These included a complete blood count, 27 serum 
chemistries, and anthropometric data including vital signs and % body fat.  On all 65 variables, 
group means fell within the normal clinical range.  The authors concluded that that long-term 
creatine supplementation does not result in adverse health effects [112]. 
Evidence to date suggests that even aged, debilitated, medically fragile patients are able 
to tolerate creatine supplementation.  Bender and colleagues studied elderly patients with 
Parkinson Disease who had received either placebo or 4 grams/day of creatine for two years.  
They found no differences between the creatine and placebo groups in laboratory markers of 
renal dysfunction [113].  Interestingly, the participants who received creatine performed better 
on the depression subscale of the Unified Parkinson Disease Rating Scale [114]. 
In a placebo-controlled trial of 104 patients with Amyotrophic Lateral Sclerosis lasting 6 
months at a dose of 5 grams/day, the authors reported that no serious or non-serious adverse 
events could be attributed to study drug [115].  They further reported that creatine-treated 
subjects’ serum creatinine and urea levels remained within normal limits throughout the study 
[115]. 
Shewmon and colleagues have completed a study of creatine supplementation for 
prophylaxis of muscle aches associated with lipid-lowering HMG-CoA reductase inhibitor drugs 
(a.k.a. “statins”) [http://clinicaltrials.gov/ct2/show/NCT00797407].  The investigators monitored 
kidney function tests, liver function tests and creatine kinase.  Analyzing their safety data with a 
generalized linear model, the investigators found no significant effect of creatine administration 
in terms of adverse events [116].  In 2004, Brudnak authored a literature review of the risk-
benefit ratio of creatine supplementation, noting that blinded studies do not support a difference 
in side effects between creatine and placebo [117].   
 
Safety Profile and Toxicity of Creatine in Children & Adolescents 
A recent review in Adolescent Medicine Clinics included a discussion of creatine dosing 
[118].  Recommended dosing regimens have two main formats.   The first features “loading 
doses” of 5 grams each four times daily (20 grams total per day) for 5 to 10 days, followed by 


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doses of 2 to 5 grams/day to maintain intramuscular creatine stores; other studies have shown 
that creatine stores can be maintained with between 2 and 5 grams/day, which eliminates the 
need for a loading phase [118]. 
Smith and Dahm were among the first to report systematic research on the use of 
creatine among adolescents [119].  Creatine users reported mild gastrointestinal side effects, 
including diarrhea, cramps, and decreased appetite.  In a study of twenty adolescent soccer 
players (average age 16.6 years; STD 1.9 years), Ostojic reported no adverse events at a dose 
of 30 grams per day [120]. 
 
Cancela et al. conducted a placebo-controlled trial of creatine that was designed to 
prospectively identify changes in markers of health caused by creatine supplementation.  The 
average age of participants was 19.6 + 3.5 years [121].  Creatine was administered at a dose of 
15 grams/day for 7 days, followed by 3 grams/day for 49 days.  Blood and urine were collected 
from all participants prior to ingestion of study supplements, then again after supplementation 
with creatine (or placebo) for 8 weeks.  The investigators were unable to find adverse effects on 
participants’ serum and urinary clinical health markers of liver, renal, muscular and metabolic 
function [121].  The authors reported that no gastrointestinal distress, musculoskeletal problems 
or other clinical problems were reported by participants in the creatine-treated group [121].  
 
Bourgeois and colleagues treated eleven children between the ages of 3 and 17 (mean 
7.6 years) with Acute Lymphoblastic Leukemia with creatine for 32 weeks, in an attempt to 
attenuate body fat accumulation caused by steroid administration [122].  The authors reported 
no compliance issues arose due to side effects, that no participants or parents reported adverse 
events, and no changes in laboratory measures including serum creatinine [122]. 
 
In a study of creatine for Mitochondrial Encephalopathy, Komura et al. treated five 
patients between the age of 7 and 19 years with a dose of 0.35 gram/kg of body weight/day 
[123].  The investigators reported normal laboratory tests, including complete blood count and 
liver and kidney function in all patients [123].  Parents and patients were queried at each visit for 
side effects, and none were reported [123]. 
 
Sakellaris has studied creatine supplementation to prevent complications of Traumatic 
Brain Injury (TBI) in children [124, 125].  The study randomized 39 patients between 1 and 18 
years of age with TBI to treatment with 0.4 gm/kg of body weight per day, or to treatment as 
usual for six months.  The authors found no evidence of hepatic, renal, or cardiac toxicity in the 
patients who received creatine [124].  There was no increased incidence of intracranial events 
or medical complications observed in the patients receiving creatine [124].  The investigators 
concluded that no side effects were observed due to creatine administration [125].  Interestingly, 
there was a significant difference between the creatine-treated group and the control group on 
the TBI sequela of “Fatigue” (p < 0.001).  Specifically, the proportion of children who reported 
experiencing “No Fatigue” 6 months after their TBI was significantly higher in creatine-treated 
participants than in controls (88.9% vs. 17.6%).  This is notable because “Fatigue or loss of 
energy” is one of the diagnostic criteria for Major Depressive Disorder [126]. 
 
The Cooperative International Neuromuscular Research Group conducted a randomized 
placebo-controlled trial that enrolled 50 children between the ages of 4 and 10 years with 
Duchenne Muscular Dystrophy.  The study was a 3-arm trial:  placebo vs. creatine vs. glutamine 
[127].  Participants in the creatine group received 5 gm/day for six months.  The research group 
reported that there were no significant differences in side effect profile among the three groups, 
and that creatine and glutamine were safe and well-tolerated over 6 months at the doses 
prescribed [127]. 
In summary, SSRI-resistant adolescent MDD is a public health problem that represents a 
significant unmet need.  The dietary supplement creatine is a hypothesis-driven SSRI 
augmentation strategy, and measurement of PCr with 31P-MRS has the potential to serve as a 
translational biomarker of juvenile MDD pathophysiology and treatment response.  Creatine has 
been studied as a treatment for numerous pediatric central nervous system disorders, but its 


Placebo-Controlled Creatine (NIMH R33) 
 
 
Page 10 of 34 
 
use in child psychiatry is novel.  Creatine’s gender-specific effects in animal models mandate 
that studies in youth be initially limited to female participants.  Expanding upon our group’s 
recent completion of a multidose study to establish which of four daily creatine doses offers the 
best combination of efficacy, safety and tolerability in adolescent females with SSRI-resistant 
MDD, we propose to conduct a pilot, placebo-controlled study of 10g daily adjunctive creatine, 
the dose selected from the dose-ranging trial, for adolescent females with SSRI-resistant MDD.  
We propose to examine the relationship between depression severity and cerebral PCr and to 
measure the effect size of adjunctive creatine vs. placebo on brain chemistry and clinical 
outcome in adolescent females with SSRI-resistant MDD. 
 
OBJECTIVES:  
 
The primary hypothesis is that compared to placebo, 10g of daily creatine monohydrate for eight 
weeks will be associated with significant increases in frontal lobe PCr and β-NTP 
concentrations.  A secondary hypothesis is that decreased depressive symptoms measured 
with the CDRS-R and Montgomery Asberg Depression Rating Scale (MADRS) will be 
reciprocally correlated with increased β-NTP concentrations. 
 
PARTICIPANT SELECTION CRITERIA:  
 
Thirty-three female adolescents with MDD will be randomly assigned in a 1:1 ratio to either 
treatment for eight weeks, for a total of 66 MDD participants.  Additionally, 40 healthy 
adolescents will be recruited as comparison subjects for the study.  Key inclusion, exclusion, 
and study withdrawal criteria for each subject group are summarized below. 
 
MDD SUBJECTS 
Inclusion Criteria: 
• 
Participants must be female. 
• 
Participants must be able to grant informed consent (age >18), or parent/guardian 
permission plus participant assent (age <18). 
• 
Participants must meet DSM-IV criteria for MDD, with current mood state depressed for 
>2 weeks. 
• 
Participants must be between the ages of 12 and 21. 
• 
Current CDRS-R raw score of >40 or MADRS score >25; and CGI-S score >4. 
• 
Participants may be enrolled in individual and/or group psychotherapy, if it has been 
ongoing for at least 8 weeks. 
• 
Participants must have been in treatment with an SSRI for at least 8 weeks, the last 4 of 
which were at a dosage of >20 mg per day of fluoxetine or its equivalent, e.g. 20 mg per 
day of paroxetine, 20 mg citalopram, 10 mg escitalopram, or 100 mg sertraline.  If the 
participant attempted, but could not tolerate, a dose comparable to 20 mg fluoxetine, 
they will be considered eligible.  (This definition of "Adolescent SSRI Resistant 
Depression" is modified from the NIH-sponsored, $17 million TORDIA Randomized 
Controlled Trial [http://clinicaltrials.gov/ct2/show/NCT00018902] [128].  
 
Exclusion Criteria: 
• 
Unstable co-morbid medical, neurological, or psychiatric disorder. 
• 
Current DSM-IV criteria for substance abuse or dependence (excepting 
nicotine/cigarettes). 
• 
Clinically significant suicidal or homicidal risk. 
• 
Pre-existing renal disease. 


Placebo-Controlled Creatine (NIMH R33) 
 
 
Page 11 of 34 
 
• 
Proteinuria on baseline urinalysis testing. 
• 
Pregnancy or breastfeeding. 
• 
Sexually active and unwilling to practice contraception during the study. 
• 
Contraindication to magnetic resonance imaging (e.g. ferromagnetic implant or 
claustrophobia) 
• 
History of hypersensitivity to creatine. 
• 
History of a previous failed therapeutic trial of creatine. 
• 
Participants may be outpatients or inpatients, but incarcerated persons will be excluded 
because this study is not approved for "Research Involving Prisoners." 
• 
More than 2 suicide attempts prior to the screening visit 
• 
Participants who made a suicide attempt within 6 months prior to the screening visit 
 
Study Withdrawal Criteria: 
• 
Withdrawal of parental permission, participant informed consent, or participant assent. 
• 
Onset of a psychotic disorder or bipolar disorder. 
• 
Intolerable or clinically significant side effects to creatine. 
• 
Worsening depression, as demonstrated by an increase in CDRS-R or MADRS score 
>25% from baseline. 
• 
Positive pregnancy test. 
• 
A significant change to the participant's medication or psychotherapy treatment from the 
regimen reported at their baseline/screening visit (e.g. the SSRI is discontinued). 
• 
Incarceration, as the study is not approved to conduct "Research Involving Prisoners." 
• 
If a clinically significant intracranial lesion is found by the Radiologist on a participant's 
baseline brain scan, they will be withdrawn from the study and referred for appropriate 
medical care.  
• 
The principal investigator retains the right to withdraw participants from the study without 
their permission, in the event they are unwilling or unable to maintain adherence to the 
research protocol. 
 
HEALTHY COMPARISON SUBJECTS 
Inclusion Criteria: 
• 
Participants must be able to grant informed consent (age >18), or parent/guardian 
permission plus participant assent (age <18). 
• 
Participants must be female. 
• 
Participants must be between the ages of 12 and 21 years. 
• 
Participants must not meet DSM-IV-TR criteria for a current psychiatric illness or 
substance use disorder. 
• 
Participants must have a CDRS-R score <30. 
 
Exclusion Criteria: 
• 
Unstable medical or neurological illness. 
• 
Clinically significant psychiatric or substance use disorder. 
• 
Pregnant subjects, due to the unknown effects of MRI/MRS scans on a fetus.  In 
addition, women of childbearing potential who are unable or unwilling to practice 
contraception during the study will be excluded.  Female participants who are of 
childbearing potential must have a negative urine pregnancy test before the MRI/MRS 
scan. 
• 
Participants with a contraindication to MRI/MRS scanning, such as a metallic implant. 
 


Placebo-Controlled Creatine (NIMH R33) 
 
 
Page 12 of 34 
 
Study Withdrawal Criteria: 
• 
Withdrawal of parental permission or participant assent. 
• 
Onset of a psychotic disorder or depression. 
• 
Positive pregnancy test. 
• 
A significant change to the participant's medication or psychotherapy treatment from the 
regimen reported at their baseline/screening visit, unless directed by the principal 
investigator. 
 
 
DESIGN:  
 
The proposed study will use a randomized double-blind placebo-controlled design.  Sixty-six 
participants will be randomly assigned in a 1:1 ratio to placebo or 10g of oral daily creatine 
monohydrate augmentation for eight weeks. 
 
The study's design is consistent with the acceptable ethical justifications for the use of placebo 
controls outlined in the University of Utah Institutional Review Board's (IRB's) Investigator 
Guidance on Placebo Comparators (Version B0608).  Specifically, this study fits situations #3, #4 
and #5 of the Guidance: 
 
§ "Participants are refractory to the available therapies by virtue of their past treatment 
history" (#3):  by definition, the proposed study will recruit female adolescents with SSRI-
resistant a.k.a. treatment-refractory depression.  To meet the study's inclusion criteria, 
participants must have failed an adequate trial of the standard-of-care intervention. 
§ "The study involves adding a new investigational therapy to an established effective 
therapy" (#4):  The FDA has approved the SSRI medicines fluoxetine and escitalopram to 
treat adolescent depression.  The guidelines of the American Academy of Pediatrics, and 
the American Academy of Child & Adolescent Psychiatry advocate cautious use of SSRIs 
to treat adolescents with MDD.  This is an augmentation study, meaning this protocol does 
not remove an established treatment from any participant.  All participants will not have a 
"washout period."  All participants must continue on an adequate dose of a prescription 
SSRI antidepressant throughout the time they are enrolled in the study. 
o This is similar to the Placebo Justification listed on the ERICA website, which says:  
"Any placebo use in this trial is in addition to usual and standard therapy."  The 
proposed study conforms to this criterion, as only participants whose depression has 
proven resistant to standard antidepressant treatment are eligible.  Furthermore, 
participants in the placebo group will not discontinue their SSRI prescription during 
the study.  On the contrary, they must continue the usual and standard therapy 
throughout their participation in the trial. 
§ "Participants have determined that the response to the established effective therapies for 
their condition is unsatisfactory to them" (#5):  the proposed study will only enroll 
adolescents who have had an adequate trial of a standard-of-care SSRI antidepressant 
treatment, and who continue to meet diagnostic criteria for major depression with at least 
moderate residual symptoms.  Persons who have never taken an SSRI antidepressant, or 
who consider their response to SSRI(s) to be satisfactory, will be excluded from 
participation in this study. 
 
Participants will undergo neuroimaging at baseline, prior to administration of investigational 
drug.  The neuroimaging will then be repeated following 8 weeks of study drug.  If the study 
treatment is tolerated well, after the initial 8 weeks, open-label continuation treatment with 


Placebo-Controlled Creatine (NIMH R33) 
 
 
Page 13 of 34 
 
creatine monohydrate 10g/day will be offered for 6 months. The open-label extension offers 
participants initially randomized to placebo an opportunity for a 6-month therapeutic trial of 
adjunctive creatine at no cost, with monitoring by the research team and 24/7 cellphone access 
to a board-certified child psychiatrist. Participants who elect to take 10g/day of creatine will be 
scheduled for monthly visits over the course of 6 months. At the sixth visit, repeat labs will be 
obtained. Additionally, per Dr. Kondo’s discretion, supplementary labs may be obtained 
throughout the open-label follow-up phase. 
 
STUDY PROCEDURES:  
 
All procedures performed by study personnel are research-related.  None of the study activities 
will be considered standard of care.  There will be no cost to study subjects for their 
participation.  Participants will be compensated for their time and travel.  Table 1 outlines the 
schedule of study procedures. 
 
Consent will be obtained before any study procedures are initiated. Potential participants will be 
informed of the study and offered a consent form to review. They will be encouraged to discuss 
study participation with their relatives. If a potential participants expresses interest in study 
participation, the informed consent process will be conducted. After the informed consent 
process, individuals will be offered time to consider study participation and to ask questions. 
Subjects and parents/guardians will have the opportunity to discuss the study with a study team 
member in a setting free of coercion. The language of the informed consent form is written at a 
level easily understood by the subject and any questions asked by the subject will be answered 
honestly and free of bias. A specific meeting time will be set up between a study team member 
and the participant where the entire informed consent document will be carefully explained in its 
entirety. The length of the meeting will be designed so there is the necessary amount of time for 
all questions to be answered.   
 
Randomization of participants to the two treatment conditions will take place according to a 
randomization list generated prior to the start of recruitment, by an individual (Dr. Sung) who will 
have no contact with participants or with study drug.  Thirty-three participants (50%) will be 
randomized to placebo.  The study will be conducted as a double-blind trial, with neither 
participants nor research staff aware of participant assignment.  Except in cases of medical 
emergency, the double-blind will not be "broken" until recruitment is closed and the final 
participant has completed 8 weeks of treatment with investigational drug.  There is no "washout 
period" for any participant in this study, and participants randomized to placebo will continue 
treatment with a prescription SSRI antidepressant throughout their time in the study. 
 
If during the MRI/MRS scans we unexpectedly discover something that warrants further 
inspection, we will refer the participant to her primary care provider for follow-up, along with the 
MRI/MRS report that shows the findings.  Any costs related to following up on unexpected 
findings will be the responsibility of her and/or her insurance provider. 
 
Participants will be compensated for their participation. The overall expected amount of 
compensation per MDD participant will be 245 dollars and participants will be paid at each visit. 
Payment of compensation will vary from visit to visit depending on the length of time needed for 
that session. Sessions that are scheduled to take longer (e.g., initial screenings, MRI's, and end 
of study visits) will be compensated accordingly.  In order to avoid study participation costing 
participants money due to travel expenses, participants traveling more than 100 miles round trip 
per study visit will be given an additional $50 at the week 10 visit, making their total 


Placebo-Controlled Creatine (NIMH R33) 
 
 
Page 14 of 34 
 
compensation for the study $295.  Participants that are screened but not eligible to enroll in the 
study will be compensated $25. 
 
HC participants will be paid $25 for the screening visit and $50 for the scan visit, totaling $75. 
 
Table 1: Schedule of Procedures for Major Depression (MDD) & Healthy Control (HC) 
Participants 
 
Study Week #  
- 1 
0 
1 
2 
3 
4 
6 
8 
10 
Parent / Guardian Consent and Participant 
Assent OR Participant Consent 
MDD HC 
 
 
 
 
 
 
 
 
Medical History & Physical Exam 
MDD 
 
 
 
 
 
 
 
 
Electrocardiogram, Phlebotomy for Serum Labs 
(CBC & CMP), Urinalysis*† 
MDD 
 
 
 
 
 
 
MDD 
 
Urine HCG Test & Drug Screen* 
MDD HC 
MDD HC 
 
 
 
 
 
MDD 
 
Randomization 
 
MDD 
 
 
 
 
 
 
 
Dispense Study Medication** 
 
MDD 
MDD 
MDD 
MDD 
MDD 
MDD 
 
 
KSADS-PL (< 18 years old) or SCID (> 18 years 
old) 
MDD HC 
 
 
 
 
 
 
 
 
CDRS-R, CGI, C-SSRS, MADRS, Safety Plan 
MDD HC 
MDD HC 
MDD 
MDD 
MDD 
MDD 
MDD 
MDD 
MDD 
DAS 
MDD 
 
 
 
 
 
 
MDD 
 
Vital Signs, Concomitant Meds, Adverse Events 
MDD HC 
MDD HC 
MDD 
MDD 
MDD 
MDD 
MDD 
MDD 
MDD 
3-Tesla MRI / 
31P-MRSI Brain Scan 
 
MDD HC 
 
 
 
 
 
MDD 
 
CBC = complete blood count 
CMP = comprehensive metabolic panel 
CDRS-R = Children’s Depression Rating Scale-Revised  
CGI = Clinical Global Impression Scale  
C-SSRS = Columbia-Suicide Severity Scale  
KSADS-PL = Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version  
SCID = Structured Clinical Interview for DSM-IV Disorders 
MADRS = Montgomery-Asberg Depression Rating Scale 
DAS= Dysfunctional Attitude Scale 
MRI = Magnetic Resonance Imaging 
31P-MRSI = 31-Phosphorus Magnetic Resonance Spectroscopy Imaging 
 
*May be collected at Study Week #0 only if time does not permit for the collection of these during Study Week #-1. 
 
**Participants will not begin taking study medication until serum lab and urinalysis results have been reviewed by Dr. Kondo. 
 
† Per Dr. Kondo’s discretion, additional lab tests may be ordered throughout the open-label follow-up phase. 
 


Placebo-Controlled Creatine (NIMH R33) 
 
 
Page 15 of 34 
 
Table 2: Schedule of 6-Month Follow-Up Procedures for MDD Participants 
 
Month #  
 1 
2 
3 
4 
5 
6 
Phlebotomy for Serum Labs (CBC & CMP) and 
Urinalysis † 
 
 
 
 
 
X 
Dispense Study Medication 
X 
X 
X 
X 
X 
X 
CDRS-R, CGI, C-SSRS, MADRS, Safety Plan 
X 
X 
X 
X 
X 
X 
DAS 
 
 
 
 
 
X 
Vital Signs, Concomitant Meds, Adverse 
Events* 
X 
X 
X 
X 
X 
X 
CBC = complete blood count 
CMP = comprehensive metabolic panel 
CDRS-R = Children’s Depression Rating Scale-Revised  
CGI = Clinical Global Impression Scale  
C-SSRS = Columbia-Suicide Severity Scale  
MADRS = Montgomery-Asberg Depression Rating Scale 
DAS= Dysfunctional Attitude Scale 
 
*Adverse events will not be evaluated after the follow-up portion of the study  
 
† Per Dr. Kondo’s discretion, additional lab tests may be ordered 
 
RISKS AND BENEFITS TO STUDY PARTICIPANTS 
• 
During the intake and assessment interview, participants may become emotionally upset 
when asked about their psychiatric history including suicide attempts, or physical and sexual 
abuse.  
• 
There is a 50% chance that the participant will be assigned to placebo, in which they will not 
receive creatine. 
• 
Participants may experience discomfort or swelling when blood is drawn for laboratory 
tests.  Rarely, infection can result from blood draws.  
• 
It is possible that the participant’s illness could worsen during the study. This could be 
related or unrelated to the study. Adolescents with Major Depressive Disorder are at risk for 
depression, suicidal ideation, and suicide attempts as part of their illness. Physicians 
working on the study will be available 24 hours per day. If the participant’s illness worsens to 
the point that the study doctor considers them a danger to themselves or others, they will be 
hospitalized. If the participant is hospitalized they will be withdrawn from the study. In the 
event of hospitalization, the participant or the participant’s insurance company will be 
responsible for the associated costs. 
• 
It is possible that treatment with creatine will not be effective for the participant’s depression, 
and that study participation will therefore delay the start of effective treatment. 
• 
The researchers will take precautions to safeguard the participant’s confidentiality, but it is 
possible that a breach of confidentiality could occur.  A Certificate of Confidentiality has 
been obtained for this study. 
• 
The participants may experience gastrointestinal discomfort as a result of taking study 
medication. We recommend taking the study medication with food to reduce possible 
stomach discomfort. 
• 
MRI/MRS scans do not use ionizing radiation like x-rays or CT scans.  Instead, magnetic 
fields and radio waves are used to take the pictures. There are no known risks related to 
MRI scans – other than the risk of injury when metallic objects are brought into the scanning 
room by mistake. Serious injury can occur during an MRI scan to persons who have: 
o Cardiac (heart) pacemakers. 
o Metal clips on blood vessels (also called stents). 


Placebo-Controlled Creatine (NIMH R33) 
 
 
Page 16 of 34 
 
o Artificial heart valves. 
o Artificial arms, hands, legs, etc. 
o Brain stimulator devices. 
o Implanted drug pumps. 
o Cochlear (ear) implants. 
o Ocular (eye) implants or known metal fragments in eyes. 
o Exposure to shrapnel or metal fillings 
o Other metallic surgical parts. 
o Orthodontic braces on the teeth. 
o Body jewelry or piercings that cannot be removed for the scan. 
o Certain tattoos with metallic ink (please tell us if your child has a tattoo) 
o Certain transdermal (skin) patches such as NicoDerm (nicotine for tobacco 
dependence), 
o Transderm Scop (scopolamine for motion sickness), or Ortho Evra (birth control) 
 
If the participants have any such devices, or has had a surgery where metal devices 
were placed in their body, they cannot take part in the study unless cleared for MRI 
scanning by the surgeon who implanted the medical device(s). 
 
• 
Serious risks exist if ferromagnetic objects (things that stick to magnets) are 
brought into the scanning area. These items can become dangerous flying objects, and are 
not allowed near the MRI scanner. 
• 
The FDA has approved the 3.0T scanner for routine clinical studies in children. 
The FDA has decided that MRI machines of 8T or less do not pose a risk. Although the 
scans we are using in this study have no known risks, there could be ill effects that are 
delayed, such that they have not yet been recognized by the FDA. The brain scans do not 
cause pain. Apart from the scanner noise, the participant will not know the scan is taking 
place. 
• 
Inside the scanner, some people experience claustrophobia (fear of being in 
small spaces), dizziness, headaches, or a metallic taste in the mouth. Some people 
experience double vision or see flashing lights. These symptoms are temporary, and will 
stop when the participant leaves the scanner.  
• 
The participant may feel cramped inside the scanner. There is a mirror placed 
inside the scanner so that your child can see his or her face, and look out into the scanning 
room. The technologist will be able to hear the participant at all times. 
• 
Very rarely, someone having an MRI scan feels a tingling in his or her back. 
This is due to the magnetic field changing quickly during the scan.  
• 
The precautions taken will avoid all the known risks related to MRI scans.  The 
participant can stop the scan at any time. 
 
We cannot promise any benefits to the participants from being in the study. However, there are 
some possible benefits to the participants if they participate in this study: 
• 
Participants will receive a thorough medical and psychiatric evaluation, and will be followed 
more closely than in routine clinical care. 
• 
We hope that the participant will benefit, but this cannot be guaranteed. 
 
Other than direct benefits to the participants, there are possible indirect benefits: 
• 
Results from the study will help doctors understand the way creatine affects young people 
with Major Depressive Disorder. This could help us improve treatment for female 
adolescents with depression.  


Placebo-Controlled Creatine (NIMH R33) 
 
 
Page 17 of 34 
 
• 
The brain scans may improve our understanding of the biology of depression in female 
adolescents. However, that would not directly benefit the participants. 
• 
The participants will receive a copy of the clinical MRI of their brain, if they wish. A copy of 
the MRI scan report will also go to the research team. 
 
DATA SAFETY AND MONITORING: 
 
The principal investigator and study coordinator will perform monitoring of the study records on 
a continuous basis.  Unanticipated problems and adverse events that are related to the 
research, or which place participants at greater-than-expected risk, will be reported to the IRB 
within 10 working days of learning of the event.  
 
Unanticipated problems involving risk to participants or others are defined as any incident, 
experience or outcome that meets the following criteria: 
• 
Unforeseen (not expected by the researcher or the research participant) given the 
research procedures and the subject population being studied; 
• 
Related or probably related to participation in the research, or if the event or problem 
probably or definitely affects the safety, rights and welfare of current participants; and 
• 
Suggests that the research places participants or others at a greater risk of harm 
(includes physical, psychological, economic or social harm) than was previously known 
or recognized. 
 
An unexpected adverse event is any adverse event occurring in one or more subjects 
participating in a research protocol, whose nature, severity, or frequency is not consistent with 
either: 
• 
The known or foreseeable risk of adverse events associated with the procedures 
involved in the research that are described in the protocol related-documents (i.e. 
protocol, investigational brochure, consent form, or product labeling). 
• 
The expected natural progression of any underlying disease, illness or medical condition 
of the subject experiencing the adverse event. 
 
Dr. Kondo will make the initial determination if an unexpected, adverse event is related or 
unrelated to the investigational drug or a clinical or research study procedure.  An adverse event 
is “related to the research” if in the opinion of the principal investigator or co-investigator, it was 
more likely than not related to the investigational agent or intervention. 
 
Study Premature Termination / Withdrawal Criteria: 
 
Participants may withdraw from the study at any time without giving a reason.  Dr. Kondo or co-
investigators may also make study withdrawal determinations, in coordination with participants, 
their families (when appropriate), and their non-study treating clinician(s).  A subject’s 
participation in the trial will also end if any of the following criteria are met: 
 
a) If intolerable adverse effects or toxicity from the investigational drug occurs.  Any 
treatment-emergent and medically serious symptoms will be grounds for an immediate 
evaluation by a primary care or emergency department provider, depending on severity.  
After the medical evaluation, a decision will be made by the study team regarding the 
patient’s continued participation in the study.   
b) If clinically significant suicidal or homicidal ideation develops, study withdrawal will be at 
the discretion of the study team, in consultation with participants and their treating 


Placebo-Controlled Creatine (NIMH R33) 
 
 
Page 18 of 34 
 
clinician(s).  Generally, a current or recent suicide plan with a degree of intention to carry 
out the plan will be deemed clinically significant.  The investigators will work closely with 
participants' families and community clinician(s) to maintain safety, and to arrange for 
hospitalization if it is necessary.  It is the research team's experience, however, that 
suicidal ideation and attempts are not rare in the medical history of depressed 
adolescents.  Rather, they are frequently a clinical feature of the condition.  Therefore, 
withdrawal decisions will be exercised on a case-by-base basis, with the guiding principle 
that participants must be withdrawn when there is reason to believe that study 
participation is causing harm, or is no longer in their best interest. 
c) If a participant is unable or unwilling to adhere to the study protocol, the principal 
investigator retains the right to withdraw them from the study without their permission. For 
example, study medication noncompliance for more than two study visits would be 
unacceptable and the participant would be subject to withdrawal by the principal 
investigator.  
Reporting to the U.S. Food and Drug Administration (FDA) 
 
a) Terms and Definitions: 
 
1) Associated with the use of the drug. There is a reasonable possibility that the 
experience may have been caused by the investigational drug being studied. 
2) Disability. A substantial disruption of a person's ability to conduct normal life 
functions and activities of daily living (ADLs). 
3) Life-threatening adverse drug experience:  Any adverse drug experience that places 
the patient or subject, in the view of the investigator, at immediate risk of death from 
the reaction as it occurred. 
4) Serious adverse drug experience:  An adverse drug experience occurring at any 
dose that results in any of the following outcomes:  Death, a life-threatening adverse 
drug experience, hospitalization or prolongation of existing hospitalization, a 
persistent or significant disability/incapacity, or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such medical events include: allergic bronchospasm 
requiring treatment in an emergency room or at home, blood dyscrasias, or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
5) Unexpected adverse drug experience:  Any adverse drug experience, the specificity 
or severity of which is not consistent with the current investigator brochure; or, if an 
investigator brochure is not required or available, the specificity or severity of which 
is not consistent with the risk information described in the general investigational 
plan or elsewhere in the current application, as amended.  For example, under this 
definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the 
investigator brochure only referred to “elevated hepatic enzymes” or “hepatitis.” 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected 
(by virtue of greater specificity) if the investigator brochure only listed “cerebral 
vascular accidents.”  "Unexpected," as used in this definition, refers to an adverse 
drug experience that has not been previously observed (e.g., included in the 
investigator brochure) rather than from the perspective of such experience not being 


Placebo-Controlled Creatine (NIMH R33) 
 
 
Page 19 of 34 
 
anticipated from the pharmacological properties of the pharmaceutical product. 
 
b) Review of Safety Information:  
 
The principal investigator shall promptly review all information relevant to the safety of the 
drug obtained or otherwise received from any source, foreign or domestic, including 
information derived from any clinical or epidemiological investigations, animal 
investigations, commercial marketing experience, reports in the scientific literature, and 
unpublished scientific papers, as well as reports from foreign regulatory authorities that 
have not already been previously reported to the FDA. 
 
c) IND Safety Reports: 
 
 1) Written reports 
i) The principal investigator and study coordinator shall notify the FDA and all 
participating investigators in a written IND safety report of: 
 A) Any adverse experience associated with the use of the drug that is 
both serious and unexpected; or 
 B) Any finding from tests in laboratory animals that suggests a significant 
risk for human subjects including reports of mutagenicity, 
teratogenicity, or carcinogenicity. Each notification shall be made as 
soon as possible and in no event later than 15 calendar days after the 
sponsor's initial receipt of the information. Each written notification 
may be submitted on FDA Form 3500A or in a narrative format 
(foreign events may be submitted either on an FDA Form 3500A or, if 
preferred, on a CIOMS I form; reports from animal or epidemiological 
studies shall be submitted in a narrative format) and shall bear 
prominent identification of its contents, i.e., "IND Safety Report." Each 
written notification to FDA shall be transmitted to the FDA new drug 
review division in the Center for Drug Evaluation and Research or the 
product review division in the Center for Biologics Evaluation and 
Research that has responsibility for review of the IND. If FDA 
determines that additional data are needed, the agency may require 
further data to be submitted. 
 
ii) In each written IND safety report, the study team shall identify all safety reports 
previously filed with the IND concerning a similar adverse experience, and 
shall analyze the significance of the adverse experience in light of the 
previous, similar reports. 
 
iii) The study team will send an annual report 60 days within the “study may 
proceed” date. 
 
 2) Telephone and facsimile transmission safety reports. The principal investigator shall 
also notify FDA by telephone or by facsimile transmission of any unexpected fatal or 
life-threatening experience associated with the use of the drug as soon as possible 
but in no event later than 7 calendar days after the event. Each telephone call or 
facsimile transmission to FDA shall be transmitted to the FDA new drug review 
division in the Center for Drug Evaluation and Research or the product review 
division in the Center for Biologics Evaluation and Research that has responsibility 


Placebo-Controlled Creatine (NIMH R33) 
 
 
Page 20 of 34 
 
for review of the IND. 
 
 3) Reporting format or frequency. FDA may request that the principal investigator 
submit IND safety reports in a format or at a frequency different than that required 
under this paragraph. 
 
d) Follow-Up: 
 
 1) The research team shall promptly investigate all safety information received by it. 
 
 2) Follow-up information to a safety report shall be submitted as soon as the relevant 
information is available. 
 
 3) If the results of the team’s investigation show that an adverse drug experience not 
initially determined to be reportable is so reportable, the researchers shall report 
such experience in a written safety report as soon as possible, but in no event later 
than 15 calendar days after the determination is made. 
 
 4) Results of the team’s investigation of other safety information shall be submitted, as 
appropriate, in an information amendment or annual report to the FDA. 
 
Reporting to the University of Utah Institutional Review Board (IRB) 
The study team will strictly observe the University of Utah IRB policy that requires researchers 
to submit reports of events that may represent unanticipated problems (UPs) involving risks to 
participants and others, including unexpected, research-related adverse events.  Reports will be 
submitted to the IRB as soon as possible after the principal investigator learns of the event, but 
in all cases within 10 working days.  Late reports will be accompanied by a written explanation 
from the principal investigator as to why the report is tardy.  
 
The following will be reported promptly by the principal investigator to the IRB:  
 
• Unexpected, research-related adverse events; 
• Breached of confidentiality or privacy that involves real or potential risk such as unauthorized 
use or disclosure of protected health information (PHI);  
• New information indicating a change to the risks or benefits of the research, such as: 
o Reports that indicate that frequency or magnitude of harms or benefits may be different 
than initially presented to the IRB; 
o Publications that show that the risks or potential benefits of the research may be 
different than initially presented to the IRB; 
o Changes in FDA labeling or withdrawal from IND status or marketing of a drug, device, 
or biologic used in the research protocol; 
• Incarceration of a participant, because this study is not approved to enroll prisoners; 
• Complaints from participants or others involved in the research that indicate unexpected risks; 
or complaints that cannot be resolved by the research team; 
• Warning or determination letters issued by any funding agency or regulatory body including 
the Office of Human Research Protections (OHRP), the Department of Health and Human 
Services (DHHS), or the Food and Drug Administration (FDA). 
• Protocol Deviations, if they are: 
o Intended to eliminate apparent immediate hazard to a research participant; 


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o Harmful (i.e. caused harm to participants or others, or placed them at increased risk of 
harm – including physical, psychological, economic, or social harm). 
o Possible Serious Non-Compliance (defined as an act or omission to act that resulted in 
increased physical, psychological, safety, or privacy risk that compromised the rights 
and welfare of research participants) – such as deliberate or repeated failure to obtain 
prior review and approval of new protocols and on-going human participants research 
by the IRB, or deliberate or repeated failure to obtain or document informed consent 
from human participants, or deliberate or repeated omission of a description of serious 
risks of the experimental therapy when obtaining informed consent, or deliberate or 
repeated failure to limit administration of the investigational drug or device to those 
participants under the investigator’s supervision, or deliberate or repeated failure to 
maintain accurate study records, report changes to the research, or report 
unanticipated problems posing risk to subjects or others to the IRB, or deliberate or 
repeated failure to comply with the conditions placed on the study by the University, 
the IRB, sponsor, or the FDA. 
o Possible Continued Non-Compliance (defined as a pattern of repeated actions or 
omissions to act that suggests a future likelihood of recurrence and that indicates a 
deficiency in the ability or willingness to comply with Federal regulations, or the policy, 
requirements, and determinations of the University of Utah IRB governing human 
subjects research) – such as consistently late submission of continuing review or items 
that require prompt reporting, repeated failure to comply with IRB requirements for 
completion of human subjects training before initiating study procedures, repeated 
failure to submit the required documents to the IRB, repeated refusal to comply with 
IRB requests, or repeated failure to submit progress reports. 
 
Protocol Amendments: 
 
Any amendments or administrative changes in the research protocol during the period, for which 
the IRB approval has already been given, will not be initiated without submission of an 
amendment for IRB review and approval. 
 
All amendments will be submitted to the FDA for review. 
 
THE DATA SAFETY MONITORING BOARD & PLAN:   
 
The Data Safety and Monitoring Board (DSMB) and monitoring plan were created in compliance 
with the University of Utah Institutional Review Board’s (IRB’s) Investigator Guidance on Data 
Safety & Monitoring (Version L1907), the IRB’s Guidance on Ongoing Data & Safety Monitoring, 
and the NIH Policy for Data and Safety Monitoring. 
 
Components of the Monitoring Plan 
 
This plan provides specific mechanisms for monitoring Adverse Events (AEs) and the safety of 
study participants, as well as the integrity and completeness of the data. The components of the 
plan are: 
• 
The DSMB membership and qualifications 
• 
A description of the review process 
• 
A description of the reports to be produced by the DSMB 
• 
A description of the information contained in the DSMB reports 
• 
A schedule of how and when the DSMB will meet 


Placebo-Controlled Creatine (NIMH R33) 
 
 
Page 22 of 34 
 
• 
The “Stopping Criteria” for the study 
• 
The definition of “Adverse Events” and “Unanticipated Problems” 
• 
A description of how and when the DSMB will report its findings to the IRB, the FDA and 
the research team 
 
1. THE DATA AND SAFETY MONITORING BOARD 
 
The study will be conducted in compliance with National Institutes of Health (NIH) requirements 
for ensuring the safety of study participants and the validity and integrity of data.  The Data 
Safety Monitoring Board (DSMB) for the study will consist of the following individuals: 
 
 
Dr. Douglas Gray.  Dr. Gray is a national expert on adolescent suicidology, and serves as 
Medical Director of the Utah Youth Suicide Study, a multifaceted program of research with the 
goal of reducing the public health burden of youth suicide in the State of Utah.  Because suicidal 
ideation and behavior is the most serious of the anticipated adverse events for this trial of 
adolescent MDD, Dr. Gray will serve as Chairman of the DSMB. 
 
Dr. Deborah Bilder.  Dr. Bilder has devoted her career to the research and treatment of autism 
spectrum disorders, and serves as the Medical Director of the Autism Spectrum Disorder Clinic 
and the Neurobehavior HOME Program at the University of Utah.  Dr. Bilder’s long-standing 
involvement in conducting innovative and sound clinical research makes her an excellent 
candidate to serve on this board. 
 
The DSMB will serve as an independent body; the DSMB members are not investigators 
participating in the study. 
 
1.1 Functions of the Data and Safety Monitoring Board 
 
The DSMB will function as an independent body charged with monitoring the safety of study 
participants, and ensuring that the scientific goals of the study are met.  To support these goals, 
the DSMB will review data and safety monitoring reports. 
 
1.2 Monitoring of Safety Data by the DSMB and the Research Team 
 
Range of Safety Reporting by the study team to the DSMB.  The study team will provide the 
following information to the DSMB for its review on an annual basis:  Serious Adverse Events 
(SAEs), Unanticipated Adverse Events (UAEs), Adverse Events (AEs), Unanticipated Problems 
(UPs), study retention rates, reasons for early study withdrawal, and abnormal laboratory values 
that are determined to be related to study participation.  The DSMB will have access to any 
additional data it deems necessary to fulfill its mission.  The study team will respond promptly to 
any DSMB data requests. 
 
Anticipated Adverse Events 
 
Anticipated Adverse Events for this study include the following:   
• 
Emotional upset due to questions during the assessment about participants’ psychiatric 
and social histories (including current suicidal ideation, history of suicide attempts, and 
history of physical or sexual abuse);  
• 
Pain, swelling or infection due to phlebotomy for blood laboratory testing;  


Placebo-Controlled Creatine (NIMH R33) 
 
 
Page 23 of 34 
 
• 
Nausea, diarrhea, vomiting, abdominal gas or bloating, appetite changes, headache, 
edema or weight gain associated with administration of the investigational drug creatine; 
• 
Injury due to mobilization of metallic objects inadvertently brought or worn by the 
participant into the MRI scanner.  (The MRI technicians will make every effort to avoid 
this by reminding the participant and their parent or guardian to take the appropriate 
precautions prior to entering the scanning suite.  An MRI safety questionnaire must be 
completed by participants immediately prior to each scanning session.);  
• 
Claustrophobia (fear of being in small spaces), dizziness, headache, metallic taste in the 
mouth, double vision, visions of flashing lights, or tingling in the back during the MRI 
scans.  All of these events are rare, temporary and not medically dangerous. 
• 
Worsening depression, suicidal ideation, and/or suicide attempts as part of the illness of 
MDD. 
 
The effects of creatine and MRI scans on a developing fetus are unknown, so participants will 
undergo pregnancy testing, and will be withdrawn from the study if they have a positive 
pregnancy test.  Sexually active persons unwilling to practice contraception during the study will 
be excluded from participation. 
 
Unanticipated Adverse Events are defined as events associated with study participation not 
listed above.  All SAEs will be reported to the FDA, regardless of whether they are “anticipated” 
or “unanticipated.”  
 
Other Safety-Related Reports – The DSMB will also receive an annual summary report of 
treatment retention and reasons for withdrawal.   
 
Reporting of Letters or Notices Issued by the FDA – In accordance with NIH Notice OD-00-053 
and the applicable Federal law [45 CFR 74.51 (f)], the principal investigator will report to the 
NIMH (the grant awarding agency) any communication from the FDA regarding the safety of the 
investigational drug, within 72 hours of receiving it.  Immediate notification will be made by 
telephone, and a copy of the FDA correspondence will be faxed and mailed to the NIMH.  The 
FDA communications covered by 45 CFR 74.51 (f) include the following:  Warning Letters, 
Notice of Initiation of Disqualification Proceedings and Opportunity to Explain Letter (NIDPOE), 
Notice of Opportunity for Hearing (NOOH), Notice of Disqualification, Consent Agreements, and 
Clinical Hold Letters.  Simultaneous transmission will be made locally to the IRB. 
 
The study will adopt the following Stopping Rules: 
• 
At any time during the study, if the DSMB unanimously agrees that the risks to 
participants outweigh the potential benefits, the DSMB will recommend to the IRB and 
the principal investigator that the study be stopped.  The DSMB chairman will 
communicate this to the IRB and the principal investigator. 
• 
If a unanimous recommendation to stop the study is made by the DSMB, the study will 
be halted.  Recruitment will be closed, and the study team will contact all active and 
inactive study participants. The FDA, NIMH, and investigational drug manufacturer will 
also be notified.   
• 
If the study is stopped, active study participants will be instructed to discontinue the 
investigational drug, and follow-up safety visits will be scheduled for all participants. 
 
1.3 Monitoring of Data Quality by the DSMB 
 


Placebo-Controlled Creatine (NIMH R33) 
 
 
Page 24 of 34 
 
The DSMB will receive annual reports prepared by the principal investigator and the study 
coordinator on data quality and completeness.  This will include an overview of recruitment and 
retention, a summary report describing participants’ adherence to the protocol’s procedures and 
investigational drug, and a summary of the completeness and quality of the data elements 
needed to characterize the participants and their primary and secondary outcomes.  These 
reports will be used by the DSMB to evaluate the adequacy of the research team’s data capture 
and management to support a scientifically valid analysis at the study's conclusion.  The DSMB 
will make recommendations to improve data management as needed.  After reviewing the 
report, the DMSB will send a letter to the principal investigator recommending that the study 
continue, or that the study be halted due to safety concerns. All DSMB letters will be submitted 
to the IRB. 
 
METHODS, DATA ANALYSIS AND INTERPRETATION:  
 
1. Neuroimaging Protocol 
i. 
Magnetic Resonance Imaging (Siemens Trio 3T MRI system) 
 
MRI scans will be conducted twice:  at the baseline visit, and following 8 weeks of 
treatment with study drug.  The 3.0 Tesla Siemens whole-body clinical scanner (Siemens 
Medical Solutions, Erlangen, Germany) located within the University Neuropsychiatric Institute 
(UNI) will be used to acquire this data. Participants will first undergo a routine anatomic MRI 
protocol, which includes MRI images acquired in the axial and coronal planes. Specifically, the 
anatomic scan protocol consists of a T1 weighted structural scan (MPRAGE), and double-echo 
T2 weighted scan, and a Fluid Attenuated Inversion Recovery scan (FLAIR). The purposes of 
the MR anatomic screening session include screening subjects for gross structural 
abnormalities and acquiring images for use in brain cortical thickness measurements. Anatomic 
MRI examinations will be performed with a quadrature radio-frequency coil. After localization, 
anatomical imaging will be obtained using a T1-weighted, sagittal oriented 3D-Magnetization 
Prepared Rapid Gradient Echo (MPRAGE) sequence (TR/TE/TI 2100/3.97/1100 ms, matrix 
256x256, FOV 256x256 mm, flip angle 12 degree, slice thickness 1.5 mm, slab 192 mm, 
bandwidth 190 Hz/pixel). Axial proton-density and T2 weighted images will be acquired to 
screen for brain structural abnormalities using 2D Double echo T2 weighted turbo spin echo 
(TSE) sequence (TR 7110 ms, TE 28/84 ms, FOV 240x210, slice thickness 3 mm, flip 150°, 
bandwidth 179 Hz/pixel). FLAIR sequence (TR/TE/TI 8000/90/2500 ms, slice thickness 5 mm, 
FOV 240x168, voxel size 0.8x0.6x5.0 mm, bandwidth 200 Hz/pixel, turbo factor 13) will be used 
to detect juxtacortical-cortical lesions. All anatomic MRI images will be read by a board-certified 
Radiologist to screen for structural abnormalities.  
 
ii. 
Measurement of In-Vivo Brain Chemistry Using Phosphorus-31 Magnetic 
Resonance Spectroscopy (31P-MRS)  
a. Phosphorus MRS 
Phosphorus spectroscopy data will be acquired on the same Siemens 3T system. We 
aim to keep the duration of each MRSI examination at or under 25 minutes.  A 3D-MRSI 
sequence with elliptically weighted phase-encoding will be used to collect 31P-MRSI data to 
minimize T2 signal decay.  Acquisition parameters will be: data matrix size 16x16x8; TR 2000 
ms; tip-angle 90 degree for hard RF pulse; Rx bandwidth ±1 kHz; complex-points 1024; readout 
duration 256 ms; pre-acquisition delay 0.3ms; FOV 240x240 mm2 ; 16 NEX. 
 
iii. 
Spectral Analysis of 31P-MRS Data 
Spectroscopy will be analyzed using Liner Combination of Model Spectra (LCModel) 
[130], which analyzes an in vivo spectrum as a linear combination of model in vitro spectra from 
individual metabolite solutions. This model is fully automatic and user independent.  A nearly 


Placebo-Controlled Creatine (NIMH R33) 
 
 
Page 25 of 34 
 
model-free constrained regularization method is used for convolution and baseline.  For 
quantification, absolute metabolite concentrations (institutional units) will be estimated using the 
unsuppressed water signal as an internal concentration reference.  Also, total creatine levels will 
be used as a denominator for calculating the relative concentration for the comparison with 
previous reports.  The standard Siemens libraries of model metabolite spectra provided with 
LCModel will be used in the basis set.  The metabolites from the basis set will include alanine, 
aspartate, creatine, gamma-amino butyric acid, glucose, glutamine, glutamate, 
glycerophosphocholine, glutathione, myo-inositol, scyllo-inositol, lactate, N-acetylaspartate, N-
acetylaspartylglutamate, phosphocholine, phosphocreatine, phosphoethanolomine, scyllo-
inositol, and taurine.  For the reliability of detection, the Cramer-Rao lower bounds (CRLB) will 
be determined:  the acceptable upper limit of estimated standard deviations will be set at 20% 
[131].   
 
Post processing of 31P-MRS data will be conducted using jMRUI software (jMRUI v. 4.0, 
European Community) with the AMARES algorithm (Advanced Method for Accurate, Robust 
and Efficient Spectral fitting of MRS data with use of prior knowledge).  Before fitting the FID 
(Free-induction-decay) data, a Hamming filter will be applied to reduce signal contamination 
from neighboring voxels, with apodization of 10 Hz line broadening.  Fourier transformation, 
frequency shifts correction, and zero-order/first order phase correction as well as baseline 
correction will be applied.  The structural image-processing tool FSL (FMRIB Software Library, 
Release 4.1, The University of Oxford) will be used to account for gray matter, white matter, and 
cerebrospinal fluid (CSF), in order to correct the partial volume effects on metabolite 
concentrations.  The MRS grid will be positioned over the images in an identical fashion 
between baseline and treatment scans for each participant.  The peak area for each 31P-MRS 
metabolite will be calculated as a percentage of the total phosphorus signal.  
 
Statistical Analyses  
We hypothesize that at baseline, CDRS-R scores are negatively correlated with cerebral PCr in 
female adolescents with SSRI-resistant MDD.  We also hypotehesize that for participants whose 
MDD responds to creatine, change CDRS-R score will be inversely correlated with change in 
brain beta-NTP levels (i.e. participants who have a significant decrease intheir CDRS-R score 
will show an increase in beta-NTP). 
Both intent-to-treat (ITT; encompasses all participants who receive >1 dose of study drug) and 
protocol completer analyses will be performed.  A participant completing 8 weeks of treatment 
and both 31P-MRS scans will be considered a "completer."  Data will be expressed as mean + 
standard deviation (SD).  Group differences in demographic variables involving continuous data 
will be calculated using one-way analysis of variance.  Between-group comparisons involving 
categorical variables will be assessed using Fisher's exact test for n x k contingency tables.  A 
linear mixed model (LMM) will be used to account for the association between measurements 
(baseline and post-treatment) for each individual for the repeated measures 
analysis.  Exploratory data analysis using non-parametric statistical tests (e.g., Wilcoxon Rank-
Sum test and the Mann-Whitney U-test) will also be performed.  Statistical significance will be 
defined at the two-tailed, 0.05 level.  Sata 11 (StataCorp LP, College Station, TX) and SAS 9.2 
(SAS Institute, Cary, NC) software will be used for statistical calculations.  Confidence intervals 
for all estimated parameters will be constructed using a 95% level. 
Power Analysis and Sample Size Calculations: Calculations are based on the open-label female 
adolescent SSRI-resistant MDD creatine data obtained at our site, and our adult creatine 
studies.  All power calculations are two-tailed with an alpha level of 0.05, and were performed in 
the specialized software PASS (NCSS, Kaysville, UT).  The minimum required sample size 


Placebo-Controlled Creatine (NIMH R33) 
 
 
Page 26 of 34 
 
satisfying our hypothesis is 30 creatine-treated, 30 placebo-treated, and 30 age-matched 
healthy controls.  Assuming a 10% attrition rate for MDD subjects and a 30% attrition rate for 
healthy controls, we propose to enroll a total of 66 female adolescents with SSRI-resistant MDD 
and 40 healthy controls.   The central hypothesis and power analysis for the R33 clinical trial are 
described below. 
The hypothesis that PCr and beta-NTP levels measured with 31P-MRS will show significant 
change associated with 8 weeks of 10g daily creatine compared with placebo in female 
adolescents with SSRI-resistant MDD evaluates the significance of treatment-related 
recovery.  In our open-label creatine data, we found that female adolescents wtih SSRI-resistant 
MDD showed increased PCr and decreased beta-NTP following creatine augmentation.  The 
effect size of these changes were estimated to be approximately 1.0 (Cohen's d) with 10% 
SD.  Therefore, when we conservatively set the effect size to be 0.9; sample size of 30 per each 
group; and common SD within a group of 10%, the changes of metabolite levels between 
creatine and placebo groups will be significantly (alpha level of 0.05) detectable with 86% of 
power. 
 
ADMINISTRATIVE RESPONSIBILITIES 
 
Resources: 
The Brain Institute 
The facilities at the University of Utah that are available for the proposed research 
include the following: the Brain Institute and UNI.  The Brain Institute currently occupies 5,900 
square feet of office and laboratory space in a building in the University of Utah Research Park 
adjacent to the Health Sciences campus.  It also occupies clinical space in UNI, the site of the 
Brain Institute’s Siemens 3T MRI research scanner.  
 
Recruitment of Participants:  
 
• No “cold calls” will be made by members of the study team. 
• An informational flyer will be placed (with permission) on public bulletin boards.  The flyer will 
be submitted to the IRB for approval prior to posting.  Examples of public bulletin boards may 
include but are not limited to:  University of Utah bulletin boards (for example, the Health 
Science Education Building, the College of Nursing, the Department of Psychology, etc.), the 
Salt Lake Community College, and business frequented by adolescents and their parents.   
• An informational brochure has been created, to be displayed (with permission) in appropriate 
public areas, and to be provided to practicing mental health clinicians, pediatricians and family 
practitioners in the Salt Lake City area.  The clinicians, at their sole discretion and without 
compensation, will pass the brochure to the parent(s) or guardian(s) of adolescent clients in 
cases where they deem it appropriate.  The brochure will be submitted to the IRB for 
approval, prior to distribution to clinicians.   
• The recruitment flyer and brochure will be posted on the Brain Institute and Department of 
Psychiatry Internet websites, following approval by the IRB. 
• The principal investigator will give presentations to advocacy groups such as NAMI, in which 
the study is described and parent(s) or guardian(s) are invited to contact the principal 
investigator to learn more about the study. 
• An informational Internet website will be created and submitted to the IRB for approval.  
• An IRB-approved paragraph informing University of Utah faculty of the study will be posted in 
the faculty newsletter (FYI newsletter).  The FYI newsletter is published once a month, and 
we will submit our IRB-approved paragraph to appear in the newsletter up to 12 times per 
year.   


Placebo-Controlled Creatine (NIMH R33) 
 
 
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• A webpage describing the study and providing contact information will be uploaded onto the 
Brain Institute's website at utahbrain.org following IRB approval. 
• Study information will be provided to the UNI receiving center to encourage clinician referrals. 
If a participant calls the Brain Institute regarding study participation and reports that they were 
referred by a UNI clinician, that clinician will receive a $5 meal card to the UNI cafeteria. 
 
CONTROL OF INVESTIGATIONAL DRUG 
 
The University of Utah pharmacy’s Investigational Drug Service (IDS) will prepare the doses of 
placebo and 10g of creatine required for the study. IDS will send the study medication in a 
blinded fashion to the University of Utah Neuropsychiatric Institute (UNI). The study medication 
will be stored securely at the UNI pharmacy, where it will be stored in a climate-controlled 
environment and accessible only to pharmacy staff and research personnel.  The study will be 
conducted in compliance with all applicable FDA regulations for IND studies. 
 
The blind will be broken following the culmination of the study or at the request of a medical 
professional dealing with a medical emergency in a case in which it would help a study 
participant. IDS will be contacted in order to break the blind.  
 
DATA COLLECTION, MANAGEMENT AND PROTECTED HEALTH INFORMATION 
 
The study team will create case report forms (CRFs) for data collection.  The consent, 
permission and assent forms, CRFs, laboratory results, radiology reports, MRI registration 
forms, and other necessary documents will be filed in each study participant’s binder.  Study 
participant binders will contain protected health information such as name, date of birth, age, 
address, and phone number.  Binders will be stored in locked cabinets located in locked offices.  
Only essential study team members will have access to participant binders.   
Using a password-protected computer with access limited to study personnel, the 
research team will maintain a computerized screening and enrollment log.  Participant 
screening, eligibility status, and consent for participation status will be recorded in this log.  
Before the performance of any study procedures, potential participants (and where applicable 
their parent(s) or guardians(s)), verbal and written informed consent will be obtained.  When a 
participant is screened for study eligibility, they will be assigned a screening ID number.  The 
individual will maintain the screening ID until they have completed the screening visit.  If a 
subject is determined to be ineligible during screening, the reason for the screen failure will be 
recorded on the computerized screening and enrollment log.  Once a subject has completed 
screening enrolled for study participation, they will be assigned a subject ID number, which will 
be used to identify all of the data collected from them during the study.   
Data from CRFs will be entered into REDCap.  REDCap is a secure, web-based 
application for building and managing online surveys and databases.  No personal identifiers 
from study participants will be entered into REDCap.  Forms that have missing or inconsistent 
data will be recorded in the database; however a “missing data” code will be entered in place of 
each piece of missing or inconsistent data.  Two study team members -- the individual who 
enters the data, and a second individual monitoring data entry -- will check each CRF form 
entered into REDCap for accuracy and completeness.   
 
RECORD RETENTION 
 
In keeping with 21CFR312.57, study records will be maintained for at least two years after the 
drug is approved by the FDA or after shipment and delivery of the drug for investigational use 
has ceased and the FDA has been notified. 


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