Ignite Creation Date:
2024-05-05 @ 11:49 AM
Last Modification Date:
2024-10-26 @ 9:14 AM
Study NCT ID:
NCT00140192
Status:
COMPLETED
Last Update Posted:
2009-07-29
First Post:
2005-08-31
Brief Title:
Creatine Treatment in Psychiatric Disorders
Sponsor:
Beersheva Mental Health Center
Organization:
Beersheva Mental Health Center
Study Overview
Official Title:
Creatine as a New Treatment for SchizophreniaA Double-Blind Trial
Status:
COMPLETED
Status Verified Date:
2005-10
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 plays a pivotal role in brain energy homeostasis 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
Dechent et al 1999 studied the effect of oral creatine supplementation for 4 wk demonstrating a statistically significant increase of mean concentration of total creatine across brain regions These findings suggest the possibility of using oral creatine supplementation to modify brain high-energy phosphate metabolism in subjects with various brain disorders including schizophrenia and major depression Recently Rae et al 2003 reported that creatine supplementation for 6 weeks had a significant positive effect on both working memory and Raven matrices Several independent lines of evidence suggest the possible involvement of altered cerebral energy metabolism in schizophrenia
We are performing a double blind cross-over study of creatine in schizophrenia
Forty patients will be treated with creatine for 3 months in a double-blind crossover design Rating scales will include scales for assessing negative and positive symptoms of schizophrenia clinical global impressions scale scales for side-effects and a cognitive battery
Creatine effects on brain energy metabolism and its possible cognitive enhancing properties raise the possibility of developing a new therapeutic strategy in schizophrenia focusing on treating metabolic hypoactive brain areas including frontal regions
Dechent et al 1999 studied the effect of oral creatine supplementation for 4 wk demonstrating a statistically significant increase of mean concentration of total creatine across brain regions These findings suggest the possibility of using oral creatine supplementation to modify brain high-energy phosphate metabolism in subjects with various brain disorders including schizophrenia and major depression Recently Rae et al 2003 reported that creatine supplementation for 6 weeks had a significant positive effect on both working memory and Raven matrices Several independent lines of evidence suggest the possible involvement of altered cerebral energy metabolism in schizophrenia
We are performing a double blind cross-over study of creatine in schizophrenia
Forty patients will be treated with creatine for 3 months in a double-blind crossover design Rating scales will include scales for assessing negative and positive symptoms of schizophrenia clinical global impressions scale scales for side-effects and a cognitive battery
Creatine effects on brain energy metabolism and its possible cognitive enhancing properties raise the possibility of developing a new therapeutic strategy in schizophrenia focusing on treating metabolic hypoactive brain areas including frontal regions
Detailed Description:
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 These findings suggest the possibility of using oral creatine supplementation to modify brain high-energy phosphate metabolism in subjects with various brain disorders including schizophrenia and major depression where alterations in brain high-energy phosphate metabolism have been reported
Kieburtz et al see httpwwwhuntington-study-grouporgCreatine20abstracthtm are conducting a double blind clinical trial of creatine in 50 ambulatory Huntington disease subjects randomized to creatine or placebo Those randomized to creatine receive 3g for 2 months and then 5g for an additional 2 months There have been no significant adverse events associated with creatine or significant changes in laboratory tests or vital signs In the creatine treated group creatine plasma levels approximately doubled 210 335 µM vs 500 125 µM Kieburtz et al are currently also conducting a multi-center double-blind study of creatine in patients with Parkinsons disease funded by the National Institute of Neurological Disorders and Stroke NINDS Recently Rae et al 2003 reported that creatine supplementation 5 grams per day for 6 weeks had a significant positive effect p 00001 on both working memory backward digit span and Ravens Advanced Progressive Matrices These findings suggest a role of brain energy capacity in influencing brain cognitive performance and that creatine via its effects on brain energy metabolism may exert beneficial effects on cognition
Several independent lines of evidence suggest the possible involvement of altered cerebral energy metabolism in the pathophysiology of schizophrenia Imaging studies have used positron emission tomography PET with flurodeoxyglucose FDG or functional magnetic resonance imaging fMRI 15O magnetic resonance spectroscopy with 31P 31P-MRS and single photon emission tomography SPECT to investigate cerebral metabolic rates in schizophrenia Most but not all studies reveal decreased metabolism in the frontal cortex in schizophrenia which was termed hypofrontality Several studies also observed alterations in brain metabolic rates in other brain regions including the temporal lobes the thalamus and the basal ganglia leading to the suggestion of an impairment in the fronto-striatal-thalamic circuitry in schizophrenia rather than in a specific brain region Andreasen et al 1997 A direct link to phosphocreatine and ATP energy systems came from studies using 31P-MRS with or without chemical shift imaging which enabled the measurement of ATP phosphocreatine and inorganic phosphate These studies showed reduced ATP in the frontal lobe and in left temporal lobe of schizophrenic patients as compared to controls Volz et al 2000 Altered brain energy metabolism could be due to impairment of mitochondria and a variety of studies reviewed recently by Ben Shachar 2002 suggest impaired mitochondrial energy metabolism in schizophrenia
Interestingly creatine besides its energy sparing properties was also shown to have neuroprotective properties in a variety of animal models for brain diseases including Huntington and Parkinson diseases as well as exerting protective effects in animal models for cerebral hypoxia Persky Brazeua 2001
We are performing a double blind cross-over study of creatine in schizophrenia
Forty consenting schizophrenic patients 18-60 years old physically healthy with more than 2 years of illness in a stable condition no gross changes in clinical presentation in the last 6 months as judged by the patients psychiatrist and presenting negative and cognitive symptoms as judged by the patients psychiatrist along with score in at least 3 items of the PANSS negative subscale 4 points while items of the PANSS positive subscale scored 3 points These patients will be recruited into the study over two years
Excluded will be patients with alcohol or drug abuse in the 6 months prior to entry into the study or any clinically significant medical condition or laboratory abnormality
Twenty patients will be treated with creatine for 3 months 3 g daily in the first month and then 5 g daily for another 2 months and then for 3 months with placebo The other twenty patients will be administered placebo for 3 months and then creatine for 3 months in the same dosages and procedure Patients neuroleptic treatment will not be affected by study participation Mood stabilizers benzodiazepines and anticholinergic medications are allowed but doses will be documented throughout the study Routine blood tests including kidney function liver function as well as plasma creatine and creatinine will be monitored at baseline and monthly throughout the study
Positive and Negative Syndrome Scale PANSS Clinical Global Impressions CGI and Adverse effectside effects assessment will be administered at baseline and then monthly A Cognitive Battery will be administered at baseline three months and six months consisting of the California Verbal Learning Test Trail making AB Purdue Pegboard Digit Symbol Coding Continuous performance test Reaction Time performance Test and Wisconsin Card Sort Test
Power Analysis We have demonstrated significant effects as add-on in schizophrenia in this design with folate treatment as a homocysteine lowering strategy in schizophrenia A sample of 36 subjects recruited over 24 months showed a statistically significant clinically relevant difference between the active treatment and placebo in a similar design to that proposed here
Creatine administration is safe with a paucity of side effects Creatine effects on brain energy metabolism and its possible cognitive enhancing properties raise the possibility of developing a new therapeutic strategy in schizophrenia focusing on treating metabolic and energetic hypoactive brain areas including frontal regions My personal research experience and position at the Beersheva Mental Health Centre make such a trial eminently feasible
REFERENCES
Andreasen NC OLeary DS Flaum M Nopoulos P Watkins GL Boles Ponto LL et al Hypofrontality in schizophrenia distributed dysfunctional circuits in neuroleptic-naive patients Lancet 1997 349 1730-4
Ben-Shachar D Mitochondrial dysfunction in schizophrenia a possible linkage to dopamine J Neurochem 2002 83 1241-51
Dechent P Pouwels PJ Wilken B Hanefeld F Frahm J Increase of total creatine in human brain after oral supplementation of creatine-monohydrate Am J Physiol 1999 277 R698-704
Lyoo IK Kong SW Sung SM Hirashima F Parow A Hennen J 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
Persky AM Brazeau GA Clinical pharmacology of the dietary supplement creatine monohydrate Pharmacol Rev 2001 53 161-76
Rae C Digney AL McEwan SR Bates TC Oral creatine monohydrate supplementation improves brain performance a double-blind placebo-controlled cross-over trial Proc R Soc Lond B Biol Sci 2003 270 2147-50
Volz H Gaser C Sauer H Supporting evidence for the model of cognitive dysmetria in schizophrenia--a structural magnetic resonance imaging study using deformation-based morphometry Schizophr Res 2000 46 45-56
Wyss M Kaddurah-Daouk R Creatine and creatinine metabolism Physiol Rev 2000 80 1107-213
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 These findings suggest the possibility of using oral creatine supplementation to modify brain high-energy phosphate metabolism in subjects with various brain disorders including schizophrenia and major depression where alterations in brain high-energy phosphate metabolism have been reported
Kieburtz et al see httpwwwhuntington-study-grouporgCreatine20abstracthtm are conducting a double blind clinical trial of creatine in 50 ambulatory Huntington disease subjects randomized to creatine or placebo Those randomized to creatine receive 3g for 2 months and then 5g for an additional 2 months There have been no significant adverse events associated with creatine or significant changes in laboratory tests or vital signs In the creatine treated group creatine plasma levels approximately doubled 210 335 µM vs 500 125 µM Kieburtz et al are currently also conducting a multi-center double-blind study of creatine in patients with Parkinsons disease funded by the National Institute of Neurological Disorders and Stroke NINDS Recently Rae et al 2003 reported that creatine supplementation 5 grams per day for 6 weeks had a significant positive effect p 00001 on both working memory backward digit span and Ravens Advanced Progressive Matrices These findings suggest a role of brain energy capacity in influencing brain cognitive performance and that creatine via its effects on brain energy metabolism may exert beneficial effects on cognition
Several independent lines of evidence suggest the possible involvement of altered cerebral energy metabolism in the pathophysiology of schizophrenia Imaging studies have used positron emission tomography PET with flurodeoxyglucose FDG or functional magnetic resonance imaging fMRI 15O magnetic resonance spectroscopy with 31P 31P-MRS and single photon emission tomography SPECT to investigate cerebral metabolic rates in schizophrenia Most but not all studies reveal decreased metabolism in the frontal cortex in schizophrenia which was termed hypofrontality Several studies also observed alterations in brain metabolic rates in other brain regions including the temporal lobes the thalamus and the basal ganglia leading to the suggestion of an impairment in the fronto-striatal-thalamic circuitry in schizophrenia rather than in a specific brain region Andreasen et al 1997 A direct link to phosphocreatine and ATP energy systems came from studies using 31P-MRS with or without chemical shift imaging which enabled the measurement of ATP phosphocreatine and inorganic phosphate These studies showed reduced ATP in the frontal lobe and in left temporal lobe of schizophrenic patients as compared to controls Volz et al 2000 Altered brain energy metabolism could be due to impairment of mitochondria and a variety of studies reviewed recently by Ben Shachar 2002 suggest impaired mitochondrial energy metabolism in schizophrenia
Interestingly creatine besides its energy sparing properties was also shown to have neuroprotective properties in a variety of animal models for brain diseases including Huntington and Parkinson diseases as well as exerting protective effects in animal models for cerebral hypoxia Persky Brazeua 2001
We are performing a double blind cross-over study of creatine in schizophrenia
Forty consenting schizophrenic patients 18-60 years old physically healthy with more than 2 years of illness in a stable condition no gross changes in clinical presentation in the last 6 months as judged by the patients psychiatrist and presenting negative and cognitive symptoms as judged by the patients psychiatrist along with score in at least 3 items of the PANSS negative subscale 4 points while items of the PANSS positive subscale scored 3 points These patients will be recruited into the study over two years
Excluded will be patients with alcohol or drug abuse in the 6 months prior to entry into the study or any clinically significant medical condition or laboratory abnormality
Twenty patients will be treated with creatine for 3 months 3 g daily in the first month and then 5 g daily for another 2 months and then for 3 months with placebo The other twenty patients will be administered placebo for 3 months and then creatine for 3 months in the same dosages and procedure Patients neuroleptic treatment will not be affected by study participation Mood stabilizers benzodiazepines and anticholinergic medications are allowed but doses will be documented throughout the study Routine blood tests including kidney function liver function as well as plasma creatine and creatinine will be monitored at baseline and monthly throughout the study
Positive and Negative Syndrome Scale PANSS Clinical Global Impressions CGI and Adverse effectside effects assessment will be administered at baseline and then monthly A Cognitive Battery will be administered at baseline three months and six months consisting of the California Verbal Learning Test Trail making AB Purdue Pegboard Digit Symbol Coding Continuous performance test Reaction Time performance Test and Wisconsin Card Sort Test
Power Analysis We have demonstrated significant effects as add-on in schizophrenia in this design with folate treatment as a homocysteine lowering strategy in schizophrenia A sample of 36 subjects recruited over 24 months showed a statistically significant clinically relevant difference between the active treatment and placebo in a similar design to that proposed here
Creatine administration is safe with a paucity of side effects Creatine effects on brain energy metabolism and its possible cognitive enhancing properties raise the possibility of developing a new therapeutic strategy in schizophrenia focusing on treating metabolic and energetic hypoactive brain areas including frontal regions My personal research experience and position at the Beersheva Mental Health Centre make such a trial eminently feasible
REFERENCES
Andreasen NC OLeary DS Flaum M Nopoulos P Watkins GL Boles Ponto LL et al Hypofrontality in schizophrenia distributed dysfunctional circuits in neuroleptic-naive patients Lancet 1997 349 1730-4
Ben-Shachar D Mitochondrial dysfunction in schizophrenia a possible linkage to dopamine J Neurochem 2002 83 1241-51
Dechent P Pouwels PJ Wilken B Hanefeld F Frahm J Increase of total creatine in human brain after oral supplementation of creatine-monohydrate Am J Physiol 1999 277 R698-704
Lyoo IK Kong SW Sung SM Hirashima F Parow A Hennen J 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
Persky AM Brazeau GA Clinical pharmacology of the dietary supplement creatine monohydrate Pharmacol Rev 2001 53 161-76
Rae C Digney AL McEwan SR Bates TC Oral creatine monohydrate supplementation improves brain performance a double-blind placebo-controlled cross-over trial Proc R Soc Lond B Biol Sci 2003 270 2147-50
Volz H Gaser C Sauer H Supporting evidence for the model of cognitive dysmetria in schizophrenia--a structural magnetic resonance imaging study using deformation-based morphometry Schizophr Res 2000 46 45-56
Wyss M Kaddurah-Daouk R Creatine and creatinine metabolism Physiol Rev 2000 80 1107-213
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