Ignite Creation Date:
2024-05-05 @ 4:48 PM
Last Modification Date:
2024-10-26 @ 9:24 AM
Study NCT ID:
NCT00313417
Status:
TERMINATED
Last Update Posted:
2013-04-05
First Post:
2006-04-11
Brief Title:
Creatine as a New Therapeutic Strategy in Depression
Sponsor:
Herzog Hospital
Organization:
Herzog Hospital
Study Overview
Official Title:
A Double-blind Parallel Randomized add-on Clinical Trial of Creatine Versus Placebo Added to Antidepressant Treatment of Patients With Major Depressive Episode
Status:
TERMINATED
Status Verified Date:
2013-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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
A double-blind parallel randomized add-on clinical trial of creatine versus placebo added to antidepressant treatment of patients with major depressive episode
Detailed Description:
DrBoris Nemetz and ProfJoseph Levine MD Beer Sheva Mental Health CenterIsrael
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 20gday for 4 wk demonstrating a significant increase of mean concentration of total creatine across brain regions 87 corresponding to 06mM P 0001 Lyoo et al 2003 studied magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatine reporting that creatine 03 gkgday for the first 7 days and 003 gkgday 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 Tab1 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 Patients 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 treatmentearly improvementand 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 12387-100
Mayberg HS Frontal lobe dysfunction in secondary depression J Neuropsychiatry Clin Neuroscience 1994 6428-442
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 Jun1586899-905
Drevets WC Bogers W Raichle ME Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism
Eur Neuropsychopharmacol 2002 Dec126527-44
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 264223-30
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 615450-8
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 14172199-2200
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 548833-9
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 4161-6
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 20gday for 4 wk demonstrating a significant increase of mean concentration of total creatine across brain regions 87 corresponding to 06mM P 0001 Lyoo et al 2003 studied magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatine reporting that creatine 03 gkgday for the first 7 days and 003 gkgday 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 Tab1 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 Patients 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 treatmentearly improvementand 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 12387-100
Mayberg HS Frontal lobe dysfunction in secondary depression J Neuropsychiatry Clin Neuroscience 1994 6428-442
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 Jun1586899-905
Drevets WC Bogers W Raichle ME Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism
Eur Neuropsychopharmacol 2002 Dec126527-44
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 264223-30
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 615450-8
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 14172199-2200
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 548833-9
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 4161-6
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None