Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT00313417 |
| Other study ID # |
Shapira1CTIL |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
Phase 4
|
| First received |
April 11, 2006 |
| Last updated |
April 3, 2013 |
| Start date |
January 2007 |
| Est. completion date |
December 2010 |
Study information
| Verified date |
April 2013 |
| Source |
Herzog Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Israel: Israeli Health Ministry Pharmaceutical Administration |
| Study type |
Interventional
|
Clinical Trial Summary
Creatine as a new therapeutic strategy in depression:
A double-blind, parallel, randomized, add-on clinical trial of creatine versus placebo added
to antidepressant treatment of patients with major depressive episode.
Description:
Dr.Boris Nemetz and Prof.Joseph Levine M.D., Beer Sheva Mental Health Center,Israel.
Creatine plays a pivotal role in brain energy homeostasis, being a temporal and spatial
buffer for cytosolic and mitochondrial pools of the cellular energy currency adenosine
triphosphate (Wyss & Kaddurah-Daouk, 2000). Recent studies have suggested increased brain
utilization of oxygen following oral creatine supplementation (Persky & Brazeua, 2001).
Creatine supplementation is widely used in enhancing sports performance, and has been tried
in the treatment of neurological, neuromuscular and atherosclerotic disease with a paucity
of side effects (Persky & Brazeua, 2001).
Creatine enters the brain via a specialized sodium dependent transporter. Dechent et al
(1999) studied the effect of oral creatine supplementation of 20g/day for 4 wk demonstrating
a significant increase of mean concentration of total creatine across brain regions (8.7%
corresponding to 0.6mM, P < 0.001). Lyoo et al (2003) studied magnetic resonance
spectroscopy of high-energy phosphate metabolites in human brain following oral
supplementation of creatine reporting that creatine (0.3 g/kg/day for the first 7 days and
0.03 g/kg/day for the next 7 days) significantly increased brain creatine levels.
Accumulated evidence suggests the possible involvement of altered cerebral energy metabolism
in the pathophysiology of depression (Mayberg, 1994). Functional brain imaging studies
(positron and single photon emission tomography) have shown decreased blood flow and
metabolism in the frontal lobes and basal ganglia in unipolar depression (Kennedy et al,
2001; Derevets et al, 2002).
Proton magnetic resonance spectroscopy studies have studied brain levels of
creatine-containing compounds. Kato et al (1992) reported that phosphocreatine was
significantly decreased in severely (as opposed to mildly) depressed patients. Dager et al
(2004) studied depressed or mixed-state bipolar patients using two-dimensional proton
echo-planar spectroscopic imaging, reporting an inverse correlation between severity of
depression and white matter creatine levels.
Finally, several studies suggest that agents with reported antidepressant activity may
increase brain levels of creatine containing compounds. Sartorius et al (2003) used MRS to
study metabolic changes in the hippocampus of rats and demonstrated a significant creatine
level rise induced by electroconvulsive shock treatment occurring specifically in the group
of animals which had exhibited depression-like [learned helplessness] behaviour before the
ECT.
S-adenosyl-L-methionine (SAM) and acetyl-L-carnitine - both reported to have antidepressant
effects - have increased brain phosphocreatine levels in healthy subjects (Silveri et al,
2003) and in geriatric depressed patients (Pettegrew et al, 2002) respectively.
Taken together, these findings suggest the possibility of using oral creatine
supplementation to increase brain levels of creatine containing compounds and therefore,
most likely by modifying high-energy phosphate metabolism in hypoactive brain areas, to
treat subjects with major depression.
Open study of creatine in depression: A preliminary open study of creatine monohydrate
(Roitman S, Green T, Osher Y, Karni N and Joseph Levine, submitted), suggested a
statistically significant beneficial effect of creatine augmentation to antidepressant
treatment in resistant major depression, but possible precipitation of a manic switch in
resistant bipolar depression (see table 1 for results). Adverse reactions were mild and
transitory and included mild nausea and flatus.
Ww propose to perform a double-blind, parallel, randomized add-on clinical trial of creatine
versus placebo added to current antidepressant treatment in the treatment of major
depressive disorder in the early phase of treatment resistant major depressive episode.
Early phase of treatment resistant depressive episode is defined where the current treatment
resistant depressive episode lasts no more than 6 months.
Based on the results of the open study presented in Tab.1, we hypothesize that such study
will show a statistically significant and clinically relevant difference between the active
treatment (creatine) and placebo in the double blind add-on trial design proposed below.
Study design
This study is a parallel, randomized, double blind, placebo controlled, 4 weeks clinical
trial examining the effect of creatine versus placebo added to antidepressant treatment of
subjects with major depression demonstrating lack of adequate response to the current
antidepressant treatment, administered in adequate dose for at least 3 weeks.
Creatine will be purchased from Solgar LTD, Israel, where 1 tablet contains 1 gram.
Forty consenting patients, women and men, 18 - 75 years old will be recruited. All subjects
will have a primary diagnosis of major depression, and at the time of recruitment will be
experiencing a major depressive episode with a duration ≥ 3 weeks and < 6 months. Subjects
will be eligible to enter the study only if they will have a minimum score of 18 points on
the 24-item Hamilton Rating Scale for Depression (HAMD) and are receiving conventional
antidepressant treatment in adequate dose for at least 3 weeks with no more than mild
improvement Blood cell count, liver and kidney functions will be performed before entering
the study, only in patients who have not had them performed during the last 6 month prior to
entering the study.
Pregnant or lactating patients, those with clinically significant or unstable medical
conditions, epilepsy, or a history of alcohol or substance abuse will be excluded from this
study. All participants will be monitored weekly and will have a 24 hours telephone access
to the researcher, and those who will develop suicidal or aggressive behaviors that may
endanger themselves or others, will be immediately discontinued from the study.
The researcher evaluating the HAM-D as well as the other study scales will be blind to the
add-on treatment (creatine or placebo). Twenty patients will be treated with creatine add-on
for 4 weeks (up to 10 grams).
The other 20 patients will be receiving placebo add-on for 4 weeks. Patient's antidepressant
treatment will not be changed during the study participation.
Benzodiazepines are allowed, but the dose will not exceed Lorazepam equivalent dose of 4 mg
daily.
The following data will be recorded at the beginning of the study:
Demographic data Psychosocial data History of hospitalizations Comorbid medical conditions
Family history of affective disorders Previous pharmacological treatments and treatment
response Seasonal pattern of depressive symptomatology
The following scales will be completed at the beginning of the study and weekly thereafter
(weeks 1 to 4):
Hamilton Depression Rating Scale (24 items) Clinical Global Impression Backwards digit span
test Scale for the assessment of side effects
The main outcome measure will be the prediction of a sustained ≥ 50 % decrease of the
Hamilton Depression Scale (HAM-D) total score versus baseline ('sustained response') and the
presence of ≥20 % HAM-D total score improvement after 1 weeks of treatment('early
improvement')and the presence of ≥50 % HAM-D total score improvement after 1 weeks of
treatment ('very early improvement') .
References
Wyss M, Kaddurah- Daouk R. Creatine and creatinine metabolism. Physiol Rev 2000; 80:
1107-213.
Persky AM, Brazeau GA. Clinical pharmacology of the dietary supplement creatine monohydrate.
Pharmac Rev 2001; 53: 161-76.
Dechent P., Pouwels PJ. Wilken B. et al. Increase of total creatine in human brain after
oral supplementation of creatine-monohydrate.
Am J Physiol 1999; 277. R698-798.
Lyoo IK, Kong SW, Hirashima F. et al. Multinuclear magnetic resonance spectroscopy of
high-energy phosphate metabolites in human brain following oral supplementation of creatine-
monohydrate.
Psychiatry Res 2003; 123:87-100.
Mayberg HS. Frontal lobe dysfunction in secondary depression. J Neuropsychiatry Clin
Neuroscience 1994; 6:428-442.
Kennedy SH, Evans KR, Kruger S, Mayberg HS, Meyer JH, McCann S, Arifuzzman AI, Houle S,
Vaccarino FJ. Changes in regional brain glucose metabolism measured with positron emission
tomography after paroxetine treatment of major depression.
Am J Psychiatry 2001 Jun;158(6):899-905.
Drevets WC, Bogers W, Raichle ME. Functional anatomical correlates of antidepressant drug
treatment assessed using PET measures of regional glucose metabolism.
Eur Neuropsychopharmacol 2002 Dec;12(6):527-44.
Kato T, Takahashi S, Shioiri T, Inubushi T: Brain phosphorous metabolism in depressive
disorders detected by phosphorus-31 magnetic resonance spectroscopy. J Affect Disord 1992;
26(4):223-30.
Dager SR, Friedman SD, Parow A, Demopulos C, Stoll AL, Lyoo IK, Dunner DL, Renshaw PF: Brain
metabolic alterations in medication-free patients with bipolar disorder.
Arch Gen Psychiatry 2004; 61(5):450-8.
Sartorius A, Vollmayr B, Neumann-Haefelin C, Ende G, Hoehn M, Henn FA: Specific creatine
rise in learned helplessness induced by electroconvulsive shock treatment.
Neuroreport 2003; 14(17):2199-2200.
Silveri MM, Parow AM, Villafuerte RA, Damico KE, Goren J, Stoll AL, Cohen BM, Renshaw PF:
S-adenosyl-L-methionine: effects on brain bioenergetic status and transverse relaxation time
in healthy subjects.
Biol Psychiatry 2003; 54(8):833-9.
Pettegrew JW, Levine J, Gershon S, Stanley JA, Servan-Schreiber D, Panchalingam K, McClure
RJ: 31P-MRS study of acetyl-L-carnitine treatment in geriatric depression: preliminary
results.
Bipolar Disord 2002; 4(1):61-6.
