Homocysteine and Creatine in Schizophrenia

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Homocysteine and Creatine in Schizophrenia
Prof. J. Levine Beer Sheva Mental Health Center,
Ben Gurion University, Beer Sheva, Israel
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Homocysteine
Illness related symptomatology Negative symptoms
Cognitive impairment
Treatment induced side effects Extrapyramidal
symptoms Glucose metabolism abnormalities
Osteoporosis
Physical morbidity CVD,
Diabetes mellitus
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HOMOCYSTINURIA

• Rare autosomal disease 1 200,000
• High blood and urine homocysteine levels
• Mental retardation, skeletal abnormalities,
  premature arteriosclerosis

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Homocysteine blood level

• Normal values 5-15 microgram/liter (µg/L)
• Moderate elevation 16-30 µg/L
• Intermediate elevation 31-100 µg/L
• Severe elevation gt100 µg/L

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Vitamin status Enzyme Deficiency B-12, folate,
B-6 Life style habits (smoking, obesity, coffee
consumption, decreased physical
activity) Age Gender Genetics (MTHFR) Drugs
CVD Renal failure Diabetes Thyroid
disease Cancer
Homocysteine Level
FACTORS EFFECTING HOMOCYSTEINE LEVEL
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Homocysteine
Illness related symptomatology Negative symptoms
Cognitive impairment
Treatment induced side effects Extrapyramidal
symptoms Glucose metabolism
abnormalities Osteoporosis
Physical morbidity CVD,
Diabetes mellitus
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Homocysteine as a risk factor for cognitive
deterioration and Alzheimer Disease
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Seshadri S, Beiser A, Selhub J, Jacques PF,
Rosenberg IH, DAgostino RB, Wilson PWF, Wolf PA
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Homocysteine may be a risk factor for several CNS
disorders

• Elevated plasma homocysteine has been found to
  be a risk factor for Alzheimer disease as well as
  for cerebral vascular disease, suggesting that
  some risk factors can accelerate or increase the
  severity of several CNS disease processes.

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Elevated Homocysteine in Mental Disorders

• Schizophrenia
• Depression
• Bipolar Disorder
• Anxiety Disorders (OCD, PTSD)
• Eating Disorders

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Proc. Natl. Acad. Sci. USA. 1997 May 27 94 (11)
59235928NeurobiologyNeurotoxicity associated
with dual actions of homocysteine at the
N-methyl-D-aspartate receptor  Lipton et al

• With physiological levels of glycine,
  homocysteine acts as a partial antagonist at the
  glycine coagonist site of the N-methyl-D-aspartate
  receptor.
• Homocysteine acts as an agonist at the
  glutamate binding site of the N-methyl-D-aspartate
  receptor, under pathological conditions in which
  glycine levels in the nervous system are
  elevated, such as stroke and head trauma. In this
  case, homocysteine neurotoxicity (agonist effect)
  at 10100 µM level outweighs its neuroprotective
  antagonist activity.

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Proc. Natl. Acad. Sci. USA. 1997 May 27 94 (11)
59235928Neurotoxicity associated with dual
actions of homocysteine at the N-methyl-D-aspartat
e receptor Stuart A. Lipton et al

• Under these conditions neuronal damage derives
  from excessive Ca influx and reactive oxygen
  generation.
• Accordingly, homocysteine neurotoxicity through
  overstimulation of N-methyl-D-aspartate receptors
  may contribute to the pathogenesis of both
  homocystinuria and modest hyperhomocysteinemia.

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• J Neurosci 2000 Sep 1520(18)6920-6Homocyst
  eine elicits a DNA damage response in neurons
  that promotes apoptosis and hypersensitivity to
  excitotoxicity.Kruman et al
• Kruman et al (2000) reported that homocysteine
  induces apoptosis in rat hippocampal neurons.
• DNA strand breaks occur rapidly after exposure to
  homocysteine and precede mitochondrial
  dysfunction, oxidative stress, and caspase
  activation.
• Homocysteine markedly increases the vulnerability
  of hippocampal neurons to excitotoxic and
  oxidative injury in cell culture and in vivo,
  suggesting a mechanism by which homocysteine may
  contribute to the pathogenesis of
  neurodegenerative disorders.

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Mean SD of determinations made in 4-6 cultures
Homocysteine induces DNA damage and apoptosis in
cultured hippocampal neurons. Cultures were
exposed for to either saline (Con) or 250 µM
homocysteine (Hom) and then were stained with
fluorescent DNA-binding dye (top) or were
photographed under phase-contrast optics
(bottom). Note the nuclear DNA condensation and
fragmentation and the neurites damage in many of
the neurons in the culture exposed to
homocysteine Kruman et al,
2000
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Hyperhomocysteinemia may promote development of
cerebral endothelial dysfunction, oxidative
stress, and the enhancement of-amyloid
peptidedependent neurotoxicity and neuronal
apoptosis. Homocysteic acid, can also cause
neuronal excitotoxicity by stimulating
N-methyl-D-aspartate receptors. In addition, the
effects of homocysteine on atherothrombosis in
the cerebral vasculature promote central nervous
system ischemia, neuronal hypoxia, and injury.
Localzo N Engl J Med editorial,346465-8,
2002
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Homocysteine
Illness related symptomatology Negative symptoms
Cognitive impairment
Treatment induced side effects Extrapyramidal
symptoms Glucose metabolism abnormalities
Osteoporosis
Physical morbidity CVD,
Diabetes mellitus
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Does Homocysteine Play a Role in Schizophrenia
?
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• An oral methionine load has classically and
  consistently been reported to exacerbate
  schizophrenia and is of course converted to
  homocysteine.
• Several authors including Regland (1997) and
  Susser (1998) suggested that high homocysteine
  levels may consist of a risk factor for
  schizophrenia.
• In order to find whether elevated homocysteine
  levels may be associated with schizophrenia we
  screened schizophrenic patients in our catchment
  area for plasma homocysteine levels.

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 Elevated Homocysteine Levels in Young Male
Schizophrenic Inatients

• Joseph Levine, Ziva Stahl, Ben Ami Sela, Slava
  Gavendo Vladimir Ruderman, RH Belmaker
•  
• Ben Gurion University of the Negev, Beer Sheva,
  Israel
• Am J Psychiat 1591790-1792, 2002

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  Total plasma homocysteine levels were
screened in 193 schizophrenic
patients compared
to 762 controls subjects
(evaluated in a screening program for employee
health).
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• Results
  
• Homoysteine levels were significantly higher
  in schizophrenia patients compared with control
  subjects
• mean homocysteine level was
• 16.3 11.8 (SD) mM in schizophrenic patients
• versus
• 10.6 3.6 (SD) mM in healthy controls.
• One-way ANCOVA with age and sex as covariants
  showed a marked effect of diagnosis on
  homocysteine levels (F135.7, df 1951,
  plt0.0001)
• The increase was almost entirely in young
  male schizophrenic patients

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Next step

• Next, we turned to explore whether the finding is
  related to poor hospital nutrition or to other
  yet unknown factors associated with
  hospitalization ?
• One way to examine it, is to study homocysteine
  levels in newly admitted schizophrenic patients.

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Plasma Homocysteine Levels in Newly Admitted
Schizophrenic Patients

• J Applebaum, Hady Shimon, B-A Sela, RH Belmaker
  and J Levine1
•  
•  
• Ben Gurion University of the Negev, Beersheva,
  Israel,
•  

J Psychiatric Research.
3 413-416, 2004
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  Total plasma total homocysteine levels were
screened in 184 Newly admitted
schizophrenic patients
versus 305 controls subjects
(evaluated in a screening program for employee
health).
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schizophrenic patients
controls

• Figure 1 Distribution of serum homocysteine
  in male schizophrenic patients versus controls

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• Homocysteine blood levels are mainly elevated
  in a sub-group of
• YOUNG MALE SCHIZOPHRENIA PATIENTS

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• Homocysteine, methylenetetrahydrofolate reductase
  and risk of schizophrenia a meta-analysis
  Muntjewerff et al
• A meta-analysis of eight retrospective studies
  (812 cases and 2113 control subjects) was carried
  out to examine the association between
  homocysteine and schizophrenia.
• A 5 mol/l higher homocysteine level was
  associated with a 70 higher risk of
  schizophrenia.
• Molecular Psychiatry (2006) 11, 143149.

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What next

• Can anything be done to lower homocysteine levels
  in schizophrenia?
• Well, elevated homocysteine can be lowered by
  oral administration of folic acid, B-12 and
  pyridoxine.
• If so, will such homocysteine lowering strategy
  be associated with clinical improvement or
  improved cognitive functioning in schizophrenia?

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Homocysteine Reducing Strategy in Schizophrenia
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 Homocysteine Reducing Strategies Improve
Symptoms in Chronic Schizophrenic Patients with
Hyperhomocysteinemia Joseph Levine, MD1, Ziva
Stahl, MSc1, Ben-Ami Sela, PhD2, Vladimir
Ruderman MD1, Oleg Shumaico MD1, RH Belmaker MD1
 1Stanley Research Center Beersheva Mental
Health Center Ben Gurion University of the Negev,
Beersheva, Israel, 2The Institute of Chemical
Pathology, Sheba Medical Center, Tel-Hashomer,
Sackler Faculty of Medicine, Tel Aviv
UniversityBiol Psychiatry. 2006 160(3)265-9
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• Homocysteine lowering strategy in
  schizophrenia
• Inclusion criteria Schizophrenic patients with
  baseline homocysteine plasma levels gt15 microM/L
• Exclusion Criteria Patients with any physical
  illness or abnormality in blood chemistry
  patients with alcohol or drug abuse in the last 6
  months
• The design was a double-blind crossover with one
  capsule a day containing 2mg folic acid, 25 mg
  pyridoxine and 400 mg B-12.
• After 3 months patients were crossed over for
  another 3 months from active vitamin to placebo
  or vice versa.
• Positive and Negative Symptom Scale (PANSS) was
  used to measure severity of symptoms
• Fifty five patients entered the study. All
  patients entering the study were highly
  symptomatic but had shown no major clinical
  changes for at least one month

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Figure3 Homocysteine levelsAfirst three
months, Bsecond three months Group I (vitamins
first, then placebo) Group II (placebo first,
then vitamins)
Homo c y s t I n e
Placebo
Vitamin
µM
BL 1 2 3
BL 4 5
6
Months
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Figure1PANSS resultsAfirst three months,
Bsecond three months Group I (vitamins first,
then placebo) Group II (placebo first, then
vitamins)
P A N S S
Placebo
Vitamin
BL 1 2 3 BL
4 5 6
Months
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Figure 3 A model of life style factors
influencing schizophrenia prognosis via
hyperhomocysteinemia
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Arch Gen Psychiatry. 2007 Jan64(1)31-9.Elevated
prenatal homocysteine levels as a risk factor
for schizophrenia.Brown AS, Bottiglieri T,
Schaefer CA, Quesenberry CP Jr, Liu L, Bresnahan
M, Susser ES. DESIGN Nested case-control study
of a large birth cohort, born from 1959 through
1967 and followed up for schizophrenia from 1981
through 1997. PARTICIPANTS Cases (n 63) were
diagnosed with schizophrenia and other
schizophrenia spectrum disorders. Controls (n
122) belonged to the birth cohort and were
matched to cases on date of birth, sex, length of
time in the cohort, and availability of maternal
serum samples.. RESULTS In a model that tested
for a threshold effect of third-trimester
homocysteine levels, an elevated homocysteine
level was associated with a greater than 2-fold
statistically significant increase in
schizophrenia risk (odds ratio, 2.39 95
confidence interval, 1.18-4.81 P
.02). CONCLUSIONS These findings indicate that
elevated third-trimester homocysteine levels may
be a risk factor for schizophrenia. as a strategy
for prevention of schizophrenia in offspring.
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Homocysteine
Illness related symptomatology Negative symptoms
Cognitive impairment
Treatment induced side effects Extrapyramidal
symptoms Glucose
metabolism abnormalities Osteoporosis
Physical morbidity CVD,
Diabetes mellitus
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Does Homocysteine Play a Role in Neuroleptic
induced Drugs side effects ?
?
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Extrapyramidal Side Effects
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• J Clin Psychiatry. 2005 661558-63.
• High serum homocysteine levels in young male
  schizophrenic and schizoaffective patients with
• tardive parkinsonism and/or tardive dyskinesia.
• Lerner V, Miodownik C, Kaptsan A, Vishne T, Sela
  BA
• and Levine J.
• An elevated serum level of total homocysteine has
  been implicated as a risk factor for various
  neuropathologic states and some movement
  disorders.
• The aim of our study was to determine whether
  there is an association between serum total
  homocysteine level and the presence of tardive
  movement disorders TMD among schizophrenic and
  schizoaffective patients.

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• METHOD 58 patients with schizophrenia or
  schizoaffective disorder (DSM-IV) and TMD for at
  least 1 year (38 men, 20 women age range, 28-73
  years) were compared to a control group of 188
  patients with DSM-IV-diagnosed schizophrenia or
  schizoaffective disorder without TMD (123 men, 65
  women age range, 19-66 years) regarding serum
  total homocysteine levels.
• RESULTS Men with TMD (demonstrating tardive
  parkinsonism and/or TD) had significantly higher
  mean serum total homocysteine levels compared to
  sex- and age group-matched controls. The
  difference between groups was almost entirely
  attributable to the homocysteine levels of young
  male patients (age group, 19-40 years old) with
  TMD.
• CONCLUSION High serum total homocysteine level
  may constitute a risk factor for certain variants
  of TMD, especially in young schizophrenic or
  schizo-affective male patients. Further
  prospective studies are needed to clarify these
  findings.

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Homocysteine
Illness related symptomatology Negative symptoms
Cognitive impairment
Treatment induced side effects Extrapyramidal
symptoms Glucose metabolism abnormalities
Osteoporosis
Physical morbidity CVD,
diabetes mellitus
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Osteoporosis
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• Am J Psychiatry 163549-a-550, March 2006Letter
  to the Editor
• Osteoporosis and Schizophrenia
• JOSEPH LEVINE, and ROBERT H. BELMAKER
• Martina Hummer, M.D., et al. (2005) reported the
  occurrence of low bone mineral density in a group
  of young male subjects with schizophrenia. Levine
  et al. (2002) and Applebaum et al (2004) reported
  elevated plasma homocysteine levels in young male
  schizophrenic patients.
• Elevated homocysteine plasma levels were recently
  reported to be associated with osteoporotic bone
  fractures in the elderly in two large follow-up
  studies.
• McLean et al. (2004) analyzed blood samples
  obtained and stored from 1,999 men and women as
  part of the long-term Framingham Study. These
  researchers found that men and women in the upper
  quartile of homocysteine concentrations were
  nearly four and two times, respectively, as
  likely to later have a hip fracture in comparison
  to the lower quartile of homocysteine
  concentrations.

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• The mechanism underlying homocysteines effect on
  bone metabolism is not yet clear. However,
  several mechanisms were suggested, including that
  elevated homocysteine disturbs the cross-linking
  of collagen in bone and disturbs osteoblast
  formation.
• Thus, it is suggested that elevated homocysteine
  levels may be a mechanism of the low bone mineral
  density reported by Dr. Hummer et al. (2005)
  among young male subjects suffering from
  schizophrenia.
• References
• Hummer M, Malik P, Gasser RW, Hofer A, Kemmler G,
  Naveda RCM, Rettenbacher MA, Fleischhacker WW
  Osteoporosis in patients with schizophrenia. Am J
  Psychiatry 2005 162162167
• McLean RR, Jacques PF, Selhub J, Tucker KL,
  Samelson EJ, Broe KE, Hannan MT, Cupples LA, Kiel
  DP Homocysteine as a predictive factor for hip
  fracture in older persons. N Engl J Med 2004
  35020422049

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Homocysteine
Illness related symptomatology Negative symptoms
Cognitive impairment
Treatment induced side effects Extrapyramidal
symptoms glucose metabolism abnormalities
Osteoporosis
Physical morbidity CVD,
Diabetes mellitus
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Glucose Metabolism
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Homocysteine levels and glucose metabolism in
non-obese, non-diabetic chronic schizophrenia

• Henderson DC, Copeland PM, Nguyen DD, Borba CP,
  Cather C, Eden Evins A, Freudenreich O, Baer L,
  Goff DC.
• METHOD Subjects underwent a nutritional
  assessment and fasting plasma, serum insulin and
  homocysteine tests.
• RESULTS Males had a significantly higher
  homocysteine levels than females. Subjects with
  impaired fasting glucose had significantly higher
  homocysteine levels than those with normal
  fasting glucose
• CONCLUSION The group with impaired fasting
  glucose had higher fasting serum homocysteine
  concentrations than those with normal fasting
  glucose which supports a connection to elevated
  homocysteine an important cardiovascular risk
  factor.

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Homocysteine
Illness related symptomatology Negative symptoms
Cognitive impairment
Treatment induced side effects Extrapyramidal
symptoms Glucose metabolism abnormalities
Osteoporosis
Physical morbidity CVD,
Diabetes mellitus
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Does Homocysteine Play a Role in Cardiovascular
Morbidity Associated with Schizophrenia ?
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• Acknowledgement
• Supported by a Stanley Medical Research
  Institute Grant (RHB JL). The Stanley Medical
  Research Institute had no role in study design,
  data collection, analysis or interpretation of
  data or in writing the report or in the decision
  to submit for publication.

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Collaborators Belmaker RH Agam
Galila Ben-Ami Sela
Bersudsky Yuly
Ruderman Vladimir
Shumeiko Oleg
Babushkin I Shimon
Hady Bromberg Anna
Lerner Vladimir
Stahl Ziva
Appelbaum Julie
Beer Sheva Mental Health Center, Israel
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Creatine in Psychiatric Disorders
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Creatine
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Creatine is synthesized via guanidinoacetate that
is formed in the kidneys from Arginine
glycine Creatine is transported by the blood to
the muscle, brain and other cells.
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Creatine is degraded by non-enzymatic cyclization
to creatinine that is renally excreted. This
process leads to the loss of about 2 4 grams
of the total creatine pool (about 140 grams) per
day that have to be replaced by creatine
synthesized by the liver or taken in with the
diet.
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• Creatine is used as a storage form of high energy
  phosphate. The phosphate of ATP is transferred to
  creatine, generating creatine phosphate, through
  the action of creatine phosphokinase.
• The reaction is reversible such that when energy
  demand is high creatine phosphate donates its
  phosphate to ADP to yield ATP. Both creatine and
  creatine phosphate are found in muscle, brain and
  blood.

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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 adenosinetriphosphate
(Wyss Kaddurah-Daouk, 2000).
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• 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).

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Creatine in Huntington disease is safe,
tolerable, bioavailable in brain and reduces
serum 8OH2'dG.Hersch et alIn a randomized,
double-blind, placebo-controlled study in 64
subjects with Huntington disease (HD), 8 g/day of
creatine administered for 16 weeks was well
tolerated and safe. Serum and brain creatine
concentrations increased in the creatine-treated
group and returned to baseline after washout.
Serum 8-hydroxy-2'-deoxyguanosine (8OH2'dG)
levels, an indicator of oxidative injury to DNA,
were markedly elevated in HD and reduced by
creatine treatment. Neurology. 2006 Jan
2466(2)250-2.
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A pilot clinical trial of creatine and
minocycline in early Parkinson disease 18-month
results. NINDS NET-PD Investigators.
The NET-PD FS-1 futility study on creatine and
minocycline found neither agent futile in slowing
down the progression of disability in Parkinson
disease (PD) at 12 months using the prespecified
futility threshold. Additional 6 months of
follow-up in randomized, blinded phase II trial
of creatine (dosage, 10 g/d) and minocycline
(dosage, 200 mg/d) in subjects with early PD.
Data from this small, 18-month phase II trial of
creatine and minocycline do not demonstrate
safety concerns that would preclude a large,
phase III efficacy trial, although the decreased
tolerability of minocycline is a concern. Clin
Neuropharmacol. 2008 May-Jun31(3)141-50
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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 lt 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.
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• 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 major depression and bipolar
  disorder where alterations in brain high-energy
  phosphate metabolism have been reported.

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• Rae et al (2003) reported that creatine
  supplementation (5 grams per day for 6 weeks) had
  a significant positive effect on both working
  memory (backward digit span) and Raven's 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.

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Raven Advanced Progressive Matrices
Backward Digit Span
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Several independent lines of evidence suggest
the possible involvement of altered cerebral
energy metabolism in the pathophysiology of
schizophrenia and affective disorders.
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• Several studies also observed alterations in
  brain metabolic rates in other brain regions
  including the temporal lobes, the thalamus and
  the basal ganglia in schizophrenia.
• This led 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).

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• 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.

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• J Neurochem. 2002 Dec83(6)1241-51.
•   Mitochondrial dysfunction in schizophrenia a
  possible linkage to dopamine.
• Ben-Shachar et al

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Creatine as a New Treatment Strategy in
Schizophrenia A Double-Blind Trial

• Kaptsan A, Odessky A, Osher Y, Belmaker RH
  and Levine J
• Ben Gurion University of the Negev, Beersheva,
  Israel

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• Methods
• Twelve patients were treated with creatine
  monohydrate or placebo, each for 3 months in a
  double-blind crossover design.
• Rating scales included scales for assessing
  negative and positive symptoms of schizophrenia,
  clinical global impressions scale, scales for
  sideeffects and a cognitive battery

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Results

• Creatine treatment was not superior over placebo
  in reducing the score of PANSS, CGI and the
  neurocognitive tests applied.
• Side effects of creatine treatment were few
  and included nausea and vomiting

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Table 1 Treatment effect of creatine vs.
placebo supplementation in patients with
schizophrenia (XSEM, n10)
Treatment Effect Change Baseline Treatment Clinical Scales
F0.24 P0.6 2.2 1.8 0.6 1.5 64.7 5.1 64.3 4.5 Creatine PANSS Total
F0.24 P0.6 2.2 1.8 0.6 1.5 64.7 5.1 64.3 4.5 Placebo PANSS Total
F0.1 P0.8 0.4 0.8 -0.9 1.2 11.6 1.4 11.8 1.1 Creatine PANSS Positive
F0.1 P0.8 0.4 0.8 -0.9 1.2 11.6 1.4 11.8 1.1 Placebo PANSS Positive
F0.4 P0.6 1.5 0.8 0.8 0.6 20.7 2.0 20.1 1.6 Creatine PANSS Negative
F0.4 P0.6 1.5 0.8 0.8 0.6 20.7 2.0 20.1 1.6 Placebo PANSS Negative
F1.8 P0.2 2.0 0.9 -0.4 1.1 33.3 2.1 32.4 2.3 Creatine PANSS General
F1.8 P0.2 2.0 0.9 -0.4 1.1 33.3 2.1 32.4 2.3 Placebo PANSS General
F0.96 p0.4 0.4 0.2 0.0 0.2 4.4 0.3 4.3 0.3 Creatine CGI Severity
F0.96 p0.4 0.4 0.2 0.0 0.2 4.4 0.3 4.3 0.3 Placebo CGI Severity
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Conclusions

• This study (creatine - 5 grams daily for 3
  months) failed to report an effect of creatine
  monohydrate treatment on the symptomatology and
  cognitive functions of patients with
  schizophrenia.
• Higher doses of creatine administered for longer
  periods of time may be still effective in
  schizophrenia.
• Alternatively, creatine is suggested to globally
  enhance brain energy metabolism. This does not
  necessarily refute the future use of agents with
  more specific effects on brain energy metabolism,
  affecting hypometabolic frontal brain regions,
  whereas sparing other normal or hypermetabolic
  brain areas.

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• Creatine Monohydrate in Resistant Depression
• a preliminary study
• Roitman S, Green T, Osher Y, Karni N
• and Joseph Levine
• Faculty of Health Sciences, Ben Gurion University
  of the Negev, Beersheva, Israel

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• Accumulated evidence suggests the possible
  involvement of hypoactive prefrontal cerebral
  energy metabolism in the pathophysiology of
  unipolar and bipolar depression (Ketter et al,
  2001) as well as decreased brain creatine
  containing compounds in depressed patients (Kato
  et al,1992 Dager et al, 2004).
• In this regard, Kato et al (1992)reported
  decreased brain phosphocreatine in severely (as
  opposed to mildly) depressed patients and Dager
  et al (2004) studying depressed or mixed-state
  bipolar patients reported an inverse correlation
  between severity of depression and white matter
  creatine levels.

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• Several studies also suggest that agents with
  reported antidepressant activity may increase
  brain levels of creatine containing compounds
• Silveri et al
• S-adenosyl-L-methionine effects on brain
  bioenergetic status and transverse relaxation
  time in healthy subjects.
• Biol Psychiatry 2003 54(8)833-9.

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31P-MRS study of acetyl-L-carnitine treatment in
geriatric depression preliminary results.

• Pettegrew JW, Levine J, Gershon S et al
• Neurophysics Laboratory, Department of
  Psychiatry, School of Medicine, University of
  Pittsburgh, Pittsburgh, PA, USA.
• A 12-week study of two elderly, depressed
  subjects investigated the effect of
  acetyl-L-carnitine (ALCAR) treatment on the
  Hamilton Depression Rating Scale (HDRS) and on
  measures of high-energy phosphate and membrane
  phospholipid metabolism.
• High-energy and membrane phospholipid metabolites
  were measured by phosphorus magnetic resonance
  spectroscopic imaging (31P MRSI) analysis.
• HDRS and 31P MRSI measurements were taken at
  entry, 6 and 12 weeks for the depressed subjects.
  
• 31P MRSI analysis revealed that ALCAR treatment
  resulted in increasing levels of the prefrontal
  phosphocreatine (PCr), which correlated with
  HDRS..
• Bipolar Disord. 2002
  Feb4(1)61-6.

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Bipolar Disord. 2002 Feb4(1)61-6. 31P-MRS
study of acetyl-L-carnitine treatment in
geriatric depression preliminary
results. Pettegrew JW, Levine J, Gershon S,
Stanley JA, Servan-Schreiber D, Panchalingam K,
McClure RJ.
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• Taken together, these findings suggest the
  possibility of using oral creatine
  supplementation to increase brain creatine
  containing compounds and modify brain high-energy
  phosphate metabolism in key hypoactive brain
  areas in subjects with unipolar and bipolar
  depression.

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• Methods
• The study was an open, 4 week clinical add-on
  trial examining the effect of creatine
  monohydrate in the treatment of resistant
  depression.
• All 10 patients except one bipolar patient had
  been treated with antidepressants in adequate
  doses for at least 6 weeks prior to participation
  in the study, without any clinically significant
  improvement.
• Three patients had comorbid medically stable
  hypertension and/or diabetes mellitus type II.
  Patients had no history of alcohol or drug abuse.

91

• Methods
• Creatine monohydrate was administered for 4
  weeks (3 g. daily in the first week followed by
  5g. daily for another 3 weeks). Ongoing
  psychotropic treatment was not changed during the
  study.

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• The Hamilton Depression Scale (HDS), Hamilton
  Anxiety Scale (HAS), and Clinical Global
  Impression (CGI) scores were recorded at baseline
  and at weeks one, two, three, and four.

93

• Results
• Seven patients completed at least three weeks of
  the study. One way repeated measures ANOVA
  showed significant improvement on all scales
• Mean( SD) CGI , score decreased from 4.43(0.5)
  at baseline to 3.00(1.4), at week 4 p0.02.
• Mean( SD) HDS score decreased from 23.14(3.3) at
  baseline to 12.57(8.3) at week 4 p0.002.
• Mean( SD) HAS scores decreased from 18.71(3.1)
  at baseline to 12.00(6.2) at week 4 p0.016.
• LSD post-hoc testing revealed that each of the
  outcome measures improved significantly (plt0.012)
  over baseline by week one.

94

• Results
• Two female patients (ED ZC) showed transient
  increases in HDS scores following dose increase
  to 5 g/d. In both cases, when creatine dose was
  returned to 3 g/d, improvement was noted by the
  following week. One patient (MH) did not improve
  while on creatine treatment and withdrew from the
  study after week three.
• Three patients did not complete at least three
  weeks of the study two bipolar patients showed
  improvement of depression first but then dropped
  out due to development of mania or hypomania the
  third patient improved considerably during the
  first week and discontinued treatment.

95

• Adverse reactions were few and mild. Two
  patients complained of transient nuasea, in one
  case including transient flatus and constipation.
  These complaints disappeared by week four. .
• Follow up after termination of the study three
  of the seven completers reported a worsening of
  their depressive and anxiety symptoms. They then
  restarted creatine with considerable improvement
  in their condition within one to two weeks.

96

• Discussion
• This preliminary open label
• augmentation study of creatine monohydrate
• an agent which enhances brain energy
  metabolism- demonstrated a beneficial effect in
  the treatment of resistant depression.
• Five out of the seven completers achieved a
  reduction of greater than 50 in baseline HDS
  scores.

97

• Discussion
• Two of our subjects have shown a transient
  increase in HDS. A reduction in Cr treatment from
  5 to 3 grams was associated in these subjects
  with a renewed decrease in HDS. While only
  indicative, this may suggest an inverted U shape
  response for creatine.
• This study included two bipolar I patients. Each
  developed mania or hypomania while treated with
  Cr. Such a phenomenon may be of interest
  regarding the pathogenesis of mania. Is the
  induction of mania associated with the
  enhancement of brain energy by creatine in
  certain key brain structures? In this context,
  SAMe, an antidepressant and a precursor of
  creatine, was reported to be associated with high
  rate of manic/hypomanic switch in bipolar
  patients (Lipinski et al, 2003) and to increase
  brain phosphocreatine (Silveri et al, 1984).
• 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.
• Lipinski JF, Cohen BM, Frankenburg F, Tohen M,
  Waternaux C, Altesman R, Jones B, Harris P Open
  trial of S-adenosylmethionine for treatment of
  depression. Am J Psychiatry 1984 141(3)448-50.

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