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Homocysteine and Creatine in Schizophrenia

Homocysteine and Creatine in Schizophrenia. Prof. J. Levine Beer Sheva Mental Health Center, Ben Gurion University, Beer Sheva, Israel. Homocysteine. Illness related symptomatology Negative symptoms Cognitive impairment. Treatment induced side effects

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Homocysteine and Creatine in Schizophrenia

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  1. Homocysteine and Creatine in Schizophrenia Prof. J. Levine Beer Sheva Mental Health Center, Ben Gurion University, Beer Sheva, Israel

  2. Homocysteine Illness related symptomatology Negative symptoms Cognitive impairment Treatment induced side effects Extrapyramidal symptoms Glucose metabolism abnormalities Osteoporosis Physical morbidity CVD, Diabetes mellitus

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

  4. 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

  5. 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

  6. Illness related symptomatology Negative symptoms Cognitive impairment Homocysteine Treatment induced side effects Extrapyramidal symptoms Glucose metabolism abnormalitiesOsteoporosis Physical morbidity CVD, Diabetes mellitus

  7. Homocysteine as a risk factor for cognitive deterioration and Alzheimer Disease

  8. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D’Agostino RB, Wilson PWF, Wolf PA

  9. 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.

  10. Elevated Homocysteine in Mental Disorders Schizophrenia Depression Bipolar Disorder Anxiety Disorders (OCD, PTSD) Eating Disorders

  11. Proc. Natl. Acad. Sci. USA.1997 May 27; 94 (11): 5923–5928NeurobiologyNeurotoxicity 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.

  12. Proc. Natl. Acad. Sci. USA. 1997 May 27; 94 (11): 5923–5928Neurotoxicity 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-D-aspartate receptors may contribute to the pathogenesis of both homocystinuria and modest hyperhomocysteinemia.

  13. J Neurosci 2000 Sep 15;20(18):6920-6Homocysteine 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.

  14. 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 homocysteineKruman et al, 2000

  15. Hyperhomocysteinemia may promote development of cerebralendothelial dysfunction, oxidative stress,and the enhancement of-amyloid peptide–dependent neurotoxicity and neuronal apoptosis. Homocysteicacid, can also cause neuronalexcitotoxicity by stimulating N-methyl-D-aspartate receptors.In addition, the effects of homocysteine on atherothrombosisin the cerebral vasculature promote central nervous system ischemia,neuronal hypoxia, and injury. Localzo – N Engl J Med – editorial,346:465-8, 2002

  16. Illness related symptomatology Negative symptoms Cognitive impairment Homocysteine Treatment induced side effects Extrapyramidal symptoms Glucose metabolism abnormalities Osteoporosis Physical morbidity CVD, Diabetes mellitus

  17. Does Homocysteine Play a Role in Schizophrenia ?

  18. 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.

  19. 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

  20. Total plasma homocysteine levels were screened in:193 schizophrenic patients compared to762 controls subjects(evaluated in a screening program for employee health).

  21. 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

  22. 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.

  23. Plasma Homocysteine Levels in Newly Admitted SchizophrenicPatients 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

  24. Total plasma total homocysteine levels were screened in:184 Newly admitted schizophrenic patientsversus 305controls subjects(evaluated in a screening program for employee health).

  25. Figure 1: Distribution of serum homocysteine in male schizophrenic patients versus controls schizophrenic patients controls

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

  27. 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.

  28. 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?

  29. Homocysteine Reducing Strategy in Schizophrenia

  30. Homocysteine Reducing Strategies Improve Symptoms in Chronic Schizophrenic Patients with HyperhomocysteinemiaJoseph Levine, MD1, Ziva Stahl, MSc1, Ben-Ami Sela, PhD2, Vladimir Ruderman MD1, Oleg Shumaico MD1, RH Belmaker MD11Stanley 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 1;60(3):265-9

  31. 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

  32. Figure3: Homocysteine levelsA=first three months, B=second 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

  33. Figure1:PANSS resultsA=first three months, B=second three months Group I (vitamins first, then placebo) Group II (placebo first, then vitamins) P A N S S Placebo Vitamin Months BL 1 2 3 BL 4 5 6

  34. Figure 3: A model of life style factors influencing schizophrenia prognosis via hyperhomocysteinemia

  35. 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 schizophreniaspectrum 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.

  36. Homocysteine Illness related symptomatology Negative symptoms Cognitive impairment Treatment induced side effects Extrapyramidal symptoms Glucose metabolism abnormalities Osteoporosis Physical morbidity CVD, Diabetes mellitus

  37. Does Homocysteine Play a Role in Neuroleptic induced Drugs side effects ? ?

  38. Extrapyramidal Side Effects

  39. 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 andLevine 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 schizophrenicand schizoaffective patients.

  40. 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.

  41. Homocysteine Illness related symptomatology Negative symptoms Cognitive impairment Treatment induced side effects Extrapyramidal symptoms Glucose metabolism abnormalities Osteoporosis Physical morbidity CVD, diabetes mellitus

  42. Osteoporosis

  43. Am J Psychiatry 163:549-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.

  44. 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

  45. Homocysteine Illness related symptomatology Negative symptoms Cognitive impairment Treatment induced side effects Extrapyramidal symptoms glucose metabolism abnormalities Osteoporosis Physical morbidity CVD, Diabetes mellitus

  46. Glucose Metabolism

  47. 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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