Transcript שקופית 1

Homocysteine and
Creatine in
Schizophrenia
Prof. J. Levine
Beer Sheva Mental
Health Center,
Ben
Gurion University, Beer
Sheva, Israel
Illness related symptomatology
Negative symptoms
Cognitive impairment
Homocysteine
Treatment induced side effects
Extrapyramidal symptoms
Glucose metabolism abnormalities
Osteoporosis
Physical morbidity
CVD, Diabetes mellitus
HOMOCYSTINURIA
• Rare autosomal disease: 1: 200,000
• High blood and urine homocysteine levels
• Mental retardation, skeletal abnormalities,
premature arteriosclerosis
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:
>100 µg/L
Vitamin status
Enzyme Deficiency [B-12,
folate, B-6]
Life style habits (smoking,
CVD
Renal failure
Diabetes
Thyroid disease
Cancer
obesity, coffee consumption,
decreased physical activity)
Age
Gender
Genetics (MTHFR)
Homocysteine Level
Drugs
FACTORS EFFECTING HOMOCYSTEINE LEVEL
Illness related symptomatology
Negative symptoms
Cognitive impairment
Homocysteine
Treatment induced side effects
Extrapyramidal symptoms
Glucose metabolism abnormalities
Osteoporosis
Physical morbidity
CVD, Diabetes mellitus
Homocysteine as a
risk factor for
cognitive deterioration
and Alzheimer Disease
Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D’Agostino RB, Wilson PWF, Wolf
PA
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.
Elevated Homocysteine in Mental
Disorders
Schizophrenia
Depression
Bipolar Disorder
Anxiety Disorders (OCD, PTSD)
Eating Disorders
Proc. Natl. Acad. Sci. USA. 1997 May 27; 94 (11): 5923–5928
Neurobiology
Neurotoxicity 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 10–100 μM level outweighs its
neuroprotective antagonist activity.

Proc. Natl. Acad. Sci. USA. 1997 May 27; 94 (11): 5923–5928
Neurotoxicity associated with dual actions of homocysteine at the
N-methyl-D-aspartate 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-Daspartate receptors may contribute to the
pathogenesis of both homocystinuria and
modest hyperhomocysteinemia.
J Neurosci 2000 Sep 15;20(18):6920-6
Homocysteine 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.
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 phasecontrast optics (bottom).
Note the nuclear DNA condensation and fragmentation and
the neurites damage in many of the neurons in the culture
Hyperhomocysteinemia may promote development of cerebral
endothelial dysfunction, oxidative stress, and the enhancement ofLoscalzo J, Plasma homocysteine and Alzheimer’s disease, N Engl J
amyloid peptide–dependent neurotoxicity
and2002
neuronal apoptosis.
Med, 346; 465-468,
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,346:465-8, 2002
Illness related symptomatology
Negative symptoms
Cognitive impairment
Treatment induced side effects
Homocysteine
Extrapyramidal symptoms
Glucose metabolism abnormalities
Osteoporosis
Physical morbidity
CVD, Diabetes mellitus
Does Homocysteine
Play a Role in
Schizophrenia ?
• 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.
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 159:1790-1792, 2002
Total plasma homocysteine levels
were screened in:
193
schizophrenic patients
compared to
762
controls subjects
(evaluated in a screening program for employee health).
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 (F=135.7, df= 1;951, p<0.0001)]
The increase was almost entirely in young male
schizophrenic patients
Schizophrenic
Control
Age
M
F
M
F
18-29
15.0±9.1 (n=45)
10.5±3.0 (n=7)
8.0±3.1 (n=87)
8.9±3.1 (n=77)
30-39
19.1±15.5 (n=53)
10.8±4.7 (n=8)
9.9±3.3 (n=244)
9.7±3.0 (n=75)
40-49
20.1±13.1 (n=31)
10.8±5.1 (n=11)
12.6±4.1 (n=65) 11.3±2.7 (n=46)
50-59
12.3±4.2 (n=17)
16.1±1.5 (n=13)
13.8±3.2 (n=57) 11.3±2.3 (n=48)
60-70
17.7±5.8 (n=4)
14.8±5.2 (n=4)
15.0±2.8 (n=33) 13.1±2.9 (n=30)
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.
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
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).
80
60
40
20
schizophrenic
patients
controls
10
Aa
8
He althy M en
6
Schizophrenic Men
20
30
40
50
60
AGE
Figure 1: Distribution of serum homocysteine in
male schizophrenic patients versus controls
Homocysteine blood levels are mainly
elevated in a sub-group of
YOUNG MALE SCHIZOPHRENIA
PATIENTS
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, 143–149.
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?
Homocysteine Reducing
Strategy in
Schizophrenia
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 University
Biol Psychiatry. 2006 1;60(3):265-9
Homocysteine lowering strategy in schizophrenia
Inclusion criteria: Schizophrenic patients with baseline homocysteine
plasma levels >15 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
Figure3: Homocysteine levels
A=first three months, B=second three months
Group I (vitamins first, then placebo)
Group II (placebo first, then vitamins)
H
o
m
o
c
y
s
t
I
n
e
µM
30.0
Placebo
25.0
20.0
15.0
Vitamin
P
V
10.0
5.0
0.0
Months
Average
Average
Average
BL Average
1
2
3
of HCYB of HCY1 of HCY2 of HCY3
Average
Average
Average
BL Average
4
5
6
of
of HCY4 of HCY5 of HCY6
HCY3_2
Figure1:PANSS results
A=first three months, B=second three months
Group I (vitamins first, then placebo)
Group II (placebo first, then vitamins)
98.0
96.0
Placebo
94.0
P
A
N
S
S
92.0
Vitamin
90.0
88.0
P
V
86.0
84.0
A
ve
ra
g
e
6
ST
6
of
PA
N
ST
5
5
of
e
ra
g
ve
A
ve
A
4
PA
N
ST
4
PA
N
of
ra
g
e
of
e
ra
g
ve
A
BL
PA
N
ST
3
ST
3
e
ra
g
ve
B
3
of
PA
N
ST
2
PA
N
e
A
ve
ra
g
e
ra
g
ve
A
2
of
PA
N
of
PA
N
of
e
ra
g
ve
A
1
A
ST
B
BL
Months
ST
1
82.0
Figure 3: A model of life style factors influencing
schizophrenia prognosis via hyperhomocysteinemia
Arch Gen Psychiatry. 2007 Jan;64(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.
Illness related symptomatology
Negative symptoms
Cognitive impairment
Homocysteine
Treatment induced side effects
Extrapyramidal
symptoms
Glucose metabolism abnormalities
Osteoporosis
Physical morbidity
CVD, Diabetes mellitus
Does Homocysteine Play a
Role in Neuroleptic induced
?
Drugs side effects ?
Extrapyramidal Side Effects
J Clin Psychiatry. 2005 ;66:1558-63.
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.
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 DSMIV-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.
Illness related symptomatology
Negative symptoms
Cognitive impairment
Homocysteine
Treatment induced side effects
Extrapyramidal symptoms
Glucose metabolism abnormalities
Osteoporosis
Physical morbidity
CVD, diabetes mellitus
Osteoporosis
• Am J Psychiatry 163:549-a-550, March 2006
Letter 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.
• The mechanism underlying homocysteine’s 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; 162:162–
167
• 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; 350:2042–2049
Illness related symptomatology
Negative symptoms
Cognitive impairment
Homocysteine
Treatment induced side effects
Extrapyramidal symptoms
glucose metabolism abnormalities
Osteoporosis
Physical morbidity
CVD, Diabetes mellitus
Glucose Metabolism
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.
Illness related symptomatology
Negative symptoms
Cognitive impairment
Homocysteine
Treatment induced side effects
Extrapyramidal symptoms
Glucose metabolism abnormalities
Osteoporosis
Physical morbidity
CVD, Diabetes mellitus
Does Homocysteine Play a
Role in Cardiovascular
Morbidity Associated with
Schizophrenia ?
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.
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
Creatine in
Psychiatric
Disorders
Creatine
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.
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.
• 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.
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).
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 in Huntington disease is safe, tolerable, bioavailable
in brain and reduces serum 8OH2'dG.
Hersch et al
In 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 24;66(2):250-2.
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-Jun;31(3):141-50
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.
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 highenergy phosphate metabolism have been
reported.
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 .
Raven
Advanced
Progressive
Matrices
Backward
Digit Span
Several independent lines of evidence suggest
the possible involvement of altered cerebral energy
metabolism in the pathophysiology of schizophrenia
and affective disorders.
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).
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.
J Neurochem. 2002 Dec;83(6):1241-51.
Mitochondrial dysfunction in
schizophrenia: a possible linkage to
dopamine.
Ben-Shachar et al
Creatine as a New Treatment
Strategy in Schizophrenia :
A Double-Blind Trial
Kaptsan A, Odessky A, Osher Y, Belmaker RH
Levine J
and
Ben Gurion University of the Negev, Beersheva, Israel
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 side–effects and a cognitive
battery
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
Table 1: Treatment effect of creatine vs. placebo supplementation in
patients with schizophrenia (X±SEM, n=10)
Clinical
Scales
Treatment Baseline Change
Creatine
PANSS Total
PANSS
Positive
PANSS
Negative
PANSS
General
CGI
Severity
Placebo
Creatine
Placebo
Creatine
Placebo
Creatine
Placebo
Creatine
Placebo
64.7 + 5.1
64.3 + 4.5
2.2 + 1.8
0.6 + 1.5
Treatment Effect
F=0.24; P=0.6
11.6 + 1.4 0.4 +0.8
11.8 + 1.1 -0.9 + 1.2
F=0.1; P=0.8
20.7 + 2.0 1.5 + 0.8
20.1 + 1.6 0.8 + 0.6
F=0.4; P=0.6
33.3 + 2.1 2.0 + 0.9
32.4 + 2.3 -0.4 + 1.1
F=1.8; P=0.2
4.4 + 0.3
4.3 + 0.3
F=0.96; p=0.4
0.4 + 0.2
0.0 + 0.2
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.
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
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.
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.
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 Feb;4(1):61-6.
Bipolar Disord. 2002 Feb;4(1):61-6.
31P-MRS study of acetyl-Lcarnitine treatment in geriatric
depression: preliminary results.
Pettegrew JW, Levine J, Gershon
S, Stanley JA, Servan-Schreiber
D, Panchalingam K, McClure RJ.
• 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.
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.
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.
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.
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 [p=0.02].
Mean(+ SD) HDS score decreased from 23.14(3.3) at
baseline to 12.57(8.3) at week 4 [p=0.002].
Mean(+ SD) HAS scores decreased from 18.71(3.1) at
baseline to 12.00(6.2) at week 4 [p=0.016].
LSD post-hoc testing revealed that each of the outcome
measures improved significantly (p<0.012) over baseline
by week one.
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.
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.
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.
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: Sadenosyl-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-
Table 1. Patient characteristics and Hamilton Depression Scale scores
Diagnosis
Sex
Age
Years
Ill
Medication
MDD
MDD
MDD
M
M
F
49
30
58
16
4
42
MDD
Panic Dis.
MDD
MDD
Generalized
Anixiety Dis.
BPD-D
F
54
30
F
M
44
41
4
15
M
45
20
BPD-D
F
59
32
MDD
M
60
8
MDD
GAD
M
53
26
Venlafaxine 150mg/d
Citalopram 60mg/d
Sertraline 200mg,
reboxetine 8mg/d,
Lamotrigine 100mg/d
Clomipramine
225mg/d
Paroxetine 20mg/d
Fluoxetine 40mg/d,
Carbamazepine
600mg/d
Valproic acid
600mg/d
Nortriptyline
250mg/d, mirtazepine
30mg/d
Clomipramine
300mg/d
Paroxetine 20mg/d,
Valproic acid
600mg/d,
risperidone 1mg/d
ast value was carried forward
Hamilton Depression Scale
Baseline
1W
2W
3
4W
W
26
22
20
21
11
7
18
11
11
15
14
18
10
9
15
22
12
23
14
9
16
19
8
13
6
20
4
8
18
15
7
28
26
17
30
30
25
16
14
11
11
Withdrew
4
4
Withdrew mania
Withdrew hypomania
‡