Advancing Neuroprotective-Based Treatments for Schizophrenia

  • Michael S. RitsnerEmail author
  • Vladimir Lerner


Schizophrenia is a chronic, severe, and disabling brain disease. About one-third of all patients with schizophrenia do not respond adequately to drug treatment. Advances in neuroscience and clinical research have led to the introduction of a novel generation of compounds with neuroprotective properties. Despite numerous animal studies with promising neuroprotective agents, no successful strategy for neuroprotection from functional psychoses has been successfully demonstrated. There are two main targets for neuroprotective therapy: (1) neurodegenerative processes in schizophrenia (e.g. apoptosis, excitotoxicity, oxidative stress, stress sensitization, and alteration of neurosteroids); and (2) phenotypic presentations of illness including psychopathological symptoms, significant decline in cognition, psychosocial functioning and in health related quality of life (HRQL). In this chapter substantial information about clinical trials with neurosteroids, vitamins, and some herbal supplements with neuroprotective properties in schizophrenia is presented. Neurosteroids such as pregnenolone (PREG), dehydroepiandrosterone (DHEA) and their sulfates (PREGS and DHEAS) are reported to have a modulatory effect on neuronal excitability and synaptic plasticity. In addition, vitamins and herbal supplements are important for regular cell function, growth and development. As a rule, vitamins promote the activity of enzymes to improve their efficiency and in this role they are called coenzymes. The herbal supplements are active antioxidants with neuroptective properties. The authors hope that neuroprotective strategies will pave the way to the next generation of antipsychotic, sedative and mood stabilizer medications. The clinical effects of neuroprotective agents clearly merit further clinical trials for the treatment of mental disorders.


Clinical trial Dehydroepiandrosterone Folic acid Ginkgo biloba L-theanine Neuroptotection Omega-3 Pregnenolone Retinoids Schizophrenia Vitamin B6 Vitamin B12 Vitamin C Vitamin D Vitamin E 



Arachidonic acid


Abnormal involuntary movement scale


Barnes Akathisia rating scale


Brain-derived neurotrophic factor


Cambridge automated neuropsychological test battery


Clinical global impression severity scale


Central nervous system


Calgary scale for depression in schizophrenia


Docosahexaenoic acid


Docosahexaenoic acids






Dehydroepiandrosterone sulfate


Deoxyrybonucleic acid


Docosapentaenoic acid


Extract of gingko biloba


Eicosapentaenoic acid


Medication-induced extrapyramidal symptoms


Essential polyunsaturated fatty acids


Extrapyramidal symptom rating scale


First-generation antipsychotics


Gamma-aminobutyric acid


Gamma-aminobutyric acid receptor type A


Hamilton scale for anxiety




Hypothalamic-pituitary-adrenal axis


Low-density lipoprotein




Positive and negative symptom scale


Parkinson’s disease






Pregnenolone sulfate


Polyunsaturated fatty acids


Quality of life scale for rating the schizophrenic deficit syndrome




Scale for the assessment of negative symptoms


Scale for the assessment of positive symptoms


Simpson-Angus scale


Standard deviation


Second-generation antipsychotics


Superoxide dismutase


Tardive dyskinesia



We thank our collaborators Dr. Anatoly Gibel, Dr. Ekateryna Kovalyonok, Dr. Chanoch Miodownik, Dr. Yael Ratner, Dr. Tatyana Shleifer and Professor Abraham Weizman in the reviewed studies for fruitful cooperation. DHEA, L-theanine and vitamin B6 studies were supported by grants from the Stanley Foundation.


  1. 1.
    Berger G, Dell’Olio M, Amminger P et al (2007) Neuroprotection in emerging psychotic disorders. Early Intervent Psychiatry 1:114–127Google Scholar
  2. 2.
    Ehrenreich H, Siren AL (2001) Neuroprotection–what does it mean?–What means do we have? Eur Arch Psychiatry Clin Neurosci 251:149–151PubMedGoogle Scholar
  3. 3.
    Jarskog LF, Selinger ES, Lieberman JA, Gilmore JH (2004) Apoptotic proteins in the temporal cortex in schizophrenia: high Bax/Bcl-2 ratio without caspase-3 activation. Am J Psychiatry 161:109–115PubMedGoogle Scholar
  4. 4.
    Krebs M, Leopold K, Hinzpeter A, Schaefer M (2006) Neuroprotective agents in schizophrenia and affective disorders. Expert Opin Pharmacother 7:837–848PubMedGoogle Scholar
  5. 5.
    Susser E, Ritsner MS (2010) Brain protection in neuropsychiatric disorders: past, present and future challenges. In: Ritsner MS (ed) Brain protection in schizophrenia, mood and cognitive disorders. Springer, Dordrecht, pp 3–25Google Scholar
  6. 6.
    Ehrenreich H, Aust C, Krampe H et al (2004) Erythropoietin: novel approaches to neuroprotection in human brain disease. Metab Brain Disord 19:195–206Google Scholar
  7. 7.
    Ritsner MS (2010) Is a neuroprotective therapy suitable for schizophrenia patients? In: Ritsner MS (ed) Brain protection in schizophrenia, mood and cognitive disorders. Springer, Dordrecht, pp 343–395Google Scholar
  8. 8.
    Niizuma K, Endo H, Chan PH (2009) Oxidative stress and mitochondrial dysfunction as determinants of ischemic neuronal death and survival. J Neurochem 109(Suppl 1):133–138PubMedGoogle Scholar
  9. 9.
    Csernansky JG (2007) Neurodegeneration in schizophrenia: evidence from in vivo neuroimaging studies. Sci World J 7:135–143Google Scholar
  10. 10.
    Jarskog LF, Glantz LA, Gilmore JH, Lieberman JA (2005) Apoptotic mechanisms in the pathophysiology of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 29:846–858PubMedGoogle Scholar
  11. 11.
    Jarskog LF (2006) Apoptosis in schizophrenia: pathophysiologic and therapeutic considerations. Curr Opin Psychiatry 19:307–312PubMedGoogle Scholar
  12. 12.
    Cadet JL, Kahler LA (1994) Free radical mechanisms in schizophrenia and tardive dyskinesia. Neurosci Biobehav Rev 18:457–467PubMedGoogle Scholar
  13. 13.
    Warner DS, Sheng H, Batinic-Haberle I (2004) Oxidants antioxidants and the ischemic brain. J Exp Biol 207:3221–3231PubMedGoogle Scholar
  14. 14.
    Fendri C, Mechri A, Khiari G, Othman A, Kerkeni A, Gaha L (2006) Oxidative stress involvement in schizophrenia pathophysiology: a review. Encephale 32:244–252PubMedGoogle Scholar
  15. 15.
    Mahadik SP, Scheffer RE (1996) Oxidative injury and potential use of antioxidants in schizophrenia. Prostaglandins Leukot Essent Fatty Acids 55:45–54PubMedGoogle Scholar
  16. 16.
    Yao JK, Reddy R, McElhinny LG, van Kammen DP (1998) Reduced status of plasma total antioxidant capacity in schizophrenia. Schizophr Res 32:1–8PubMedGoogle Scholar
  17. 17.
    Virit O, Altindag A, Yumru M et al (2009) A defect in the antioxidant defense system in schizophrenia. Neuropsychobiology 60:87–93PubMedGoogle Scholar
  18. 18.
    Reddy R, Keshavan M, Yao JK (2003) Reduced plasma antioxidants in first-episode patients with schizophrenia. Schizophr Res 62:205–212PubMedGoogle Scholar
  19. 19.
    Smythies JR (1997) Oxidative reactions and schizophrenia: a review-discussion. Schizophr Res 24:357–364PubMedGoogle Scholar
  20. 20.
    Yao JK, Reddy R, van Kammen DP (1998) Reduced level of plasma antioxidant uric acid in schizophrenia. Psychiatry Res 80:29–39PubMedGoogle Scholar
  21. 21.
    Yao JK, Reddy R, van Kammen DP (2000) Abnormal age-related changes of plasma antioxidant proteins in schizophrenia. Psychiatry Res 97:137–151PubMedGoogle Scholar
  22. 22.
    Vardimon L (2000) Neuroprotection by glutamine synthetase. Isr Med Assoc J (Suppl 2):46–51Google Scholar
  23. 23.
    Deutsch SI, Rosse RB, Schwartz BL, Mastropaolo J (2001) A revised excitotoxic hypothesis of schizophrenia: therapeutic implications. Clin Neuropharmacol 24:43–49PubMedGoogle Scholar
  24. 24.
    Baulieu EE, Robel P (1998) Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) as neuroactive neurosteroids. Proc Natl Acad Sci USA 95:4089–4091PubMedGoogle Scholar
  25. 25.
    Charalampopoulos I, Tsatsanis C, Dermitzaki E et al (2004) Dehydroepiandrosterone and allopregnanolone protect sympathoadrenal medulla cells against apoptosis via antiapoptotic Bcl-2 proteins. Proc Natl Acad Sci USA 101:8209–8214PubMedGoogle Scholar
  26. 26.
    Charalampopoulos I, Tsatsanis C, Margioris AN, Castanas E, Gravanis A (2008) Dehydroepiandrosterone as endogenous inhibitor of neuronal cell apoptosis: potential therapeutic implications in neurodegenerative diseases. In: Ritsner MS, Weizman A (eds) Neuroactive steroids in brain functions, and mental health. New perspectives for research and treatment. Springer, New York, NY, pp 217–225Google Scholar
  27. 27.
    Gursoy E, Cardounel A, Kalimi M (2001) Pregnenolone protects mouse hippocampal (HT-22) cells against glutamate and amyloid beta protein toxicity. Neurochem Res 26:15–21PubMedGoogle Scholar
  28. 28.
    Maninger N, Wolkowitz OM, Reus VI, Epel ES, Mellon SH (2009) Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate DHEAS. Front Neuroendocrinol 30:65–91PubMedGoogle Scholar
  29. 29.
    Naert G, Maurice T, Tapia-Arancibia L, Givalois L (2007) Neuroactive steroids modulate HPA axis activity and cerebral brain-derived neurotrophic factor (BDNF) protein levels in adult male rats. Psychoneuroendocrinology 32:1062–1078PubMedGoogle Scholar
  30. 30.
    Ritsner MS, Gibel A, Ratner Y, Weizman A (2008) Dehydroepiandrosterone and pregnenolone alterations in schizophrenia. In: Ritsner MS, Weizman A (eds) Neuroactive steroids in brain function, behavior and neuropsychiatric disorders. Novel strategies for research and treatment. Springer, Bazel, pp 251–298Google Scholar
  31. 31.
    Takahashi Y, Lavigne JA, Hursting SD et al (2004) Using DNA microarray analyses to elucidate the effects of genistein in androgen-responsive prostate cancer cells: identification of novel targets. Mol Carcinog 41:108–119PubMedGoogle Scholar
  32. 32.
    Akan P, Kizildag S, Ormen M, Genc S, Oktem MA, Fadiloglu M (2009) Pregnenolone protects the PC-12 cell line against amyloid beta peptide toxicity but its sulfate ester does not. Chem Biol Interact 177:65–70PubMedGoogle Scholar
  33. 33.
    Bastianetto S, Ramassamy C, Poirier J, Quirion R (1999) Dehydroepiandrosterone (DHEA) protects hippocampal cells from oxidative stress-induced damage. Brain Res Mol Brain Res 66:35–41PubMedGoogle Scholar
  34. 34.
    Cardounel A, Regelson W, Kalimi M (1999) Dehydroepiandrosterone protects hippocampal neurons against neurotoxin-induced cell death: mechanism of action. Proc Soc Exp Biol Med 222:145–149PubMedGoogle Scholar
  35. 35.
    Karishma KK, Herbert J (2002) Dehydroepiandrosterone (DHEA) stimulates neurogenesis in the hippocampus of the rat, promotes survival of newly formed neurons and prevents corticosterone-induced suppression. Eur J Neurosci 16:445–453PubMedGoogle Scholar
  36. 36.
    Kimonides VG, Khatibi NH, Svendsen CN, Sofroniew MV, Herbert J (1998) Dehydroepiandrosterone(DHEA) and DHEA-sulfate (DHEAS) protect hippocampal neurons against excitatory amino acid-induced neurotoxicity. Proc Natl Acad Sci USA 95:1852–1857PubMedGoogle Scholar
  37. 37.
    Kurata K, Takebayashi M, Morinobu S, Yamawaki S (2004) beta-estradiol, dehydroepiandrosterone, and dehydroepiandrosterone sulfate protect against N-methyl-D-aspartate-induced neurotoxicity in rat hippocampal neurons by different mechanisms. J Pharmacol Exp Ther 311:237–245PubMedGoogle Scholar
  38. 38.
    Leskiewicz M, Jantas D, Budziszewska B, Lason W (2008) Excitatory neurosteroids attenuate apoptotic and excitotoxic cell death in primary cortical neurons. J Physiol Pharmacol 59:457–475PubMedGoogle Scholar
  39. 39.
    Veiga S, Garcia-Segura LM, Azcoitia I (2003) Neuroprotection by the steroids pregnenolone and dehydroepiandrosterone is mediated by the enzyme aromatase. J Neurobiol 56:398–406PubMedGoogle Scholar
  40. 40.
    Gallagher P, Ritsner MS (2009) Can the cortisol to DHEA molar ratio be used as a peripheral biomarker for schizophrenia and mood disorders? In: Ritsner MS (ed) The Handbook of neuropsychiatric biomarkers, endophenotypes and genes, vol 3, Springer, Dordrecht, pp 27–45Google Scholar
  41. 41.
    Ritsner M, Maayan R, Gibel A, Strous RD, Modai I, Weizman A (2004) Elevation of the cortisol/dehydroepiandrosterone ratio in schizophrenia patients. Eur Neuropsychopharmacol 14:267–273PubMedGoogle Scholar
  42. 42.
    Ritsner MS (ed) (2008) Neuroactive steroids in brain functions, and mental health. New perspectives for research and treatment. Springer, New York, NYGoogle Scholar
  43. 43.
    Nachshoni T, Ebert T, Abramovitch Y et al (2005) Improvement of extrapyramidal symptoms following dehydroepiandrosterone (DHEA) administration in antipsychotic treated schizophrenia patients: a randomized, double-blind placebo controlled trial. Schizophr Res 79:251–256PubMedGoogle Scholar
  44. 44.
    Ritsner MS, Gibel A, Ratner Y, Tsinovoy G, Strous RD (2006) Improvement of sustained attention and visual and movement skills, but not clinical symptoms, after dehydroepiandrosterone augmentation in schizophrenia: a randomized, double-blind, placebo-controlled, crossover trial. J Clin Psychopharmacol 26:495–499PubMedGoogle Scholar
  45. 45.
    Ritsner MS, Strous RD (2009) Neurocognitive deficits in schizophrenia are associated with alterations in blood levels of neurosteroids: a multiple regression analysis of findings from a double-blind, randomized, placebo-controlled, crossover trial with DHEA. J Psychiatr Res 44:75–80PubMedGoogle Scholar
  46. 46.
    Strous RD, Gibel A, Maayan R, Weizman A, Ritsner MS (2008) Hormonal response to dehydroepiandrosterone administration in schizophrenia: findings from a randomized, double-blind, placebo-controlled, crossover study. J Clin Psychopharmacol 28:456–459PubMedGoogle Scholar
  47. 47.
    Strous RD, Maayan R, Lapidus R et al (2003) Dehydroepiandrosterone augmentation in the management of negative, depressive, and anxiety symptoms in schizophrenia. Arch Gen Psychiatry 60:133–141PubMedGoogle Scholar
  48. 48.
    Strous RD, Stryjer R, Maayan R et al (2007) Analysis of clinical symptomatology, extrapyramidal symptoms and neurocognitive dysfunction following dehydroepiandrosterone (DHEA) administration in olanzapine treated schizophrenia patients: a randomized, double-blind placebo controlled trial. Psychoneuroendocrinology 32:96–105PubMedGoogle Scholar
  49. 49.
    Nestler JE, Barlascini CO, Clore JN, Blackard WG (1988) Dehydroepiandrosterone reduces serum low density lipoprotein levels and body fat but does not alter insulin sensitivity in normal men. J Clin Endocrinol Metab 66:57–61PubMedGoogle Scholar
  50. 50.
    Ritsner M, Gibel A, Ram E, Maayan R, Weizman A (2006) Alterations in DHEA metabolism in schizophrenia: two-month case-control study. Eur Neuropsychopharmacol 16:137–146PubMedGoogle Scholar
  51. 51.
    Ritsner MS, Gibel A, Shleifer T et al (2010) Pregnenolone and dehydroepiandrosterone as an adjunctive treatment in schizophrenia: an 8-week, double-blind, randomized, controlled, two-center, parallel-group study. J Clin Psychiatry 71(10):1351–1362PubMedGoogle Scholar
  52. 52.
    Marx CE, Keefe RS, Buchanan RW et al (2009) Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia. Neuropsychopharmacol 34:1885–1903Google Scholar
  53. 53.
    Zempleni J, Rucker RB, Suttie JW, McCormick DB (eds) (2007) Handbook of vitamins, 4th edn. CRC Press, New York, NYGoogle Scholar
  54. 54.
    Combs GF (2008) The vitamins: fundamental aspects in nutrition and health, 3rd edn. Elsevier Academic Press, BurlingtonGoogle Scholar
  55. 55.
    Sato Y, Meller R, Yang T, Taki W, Simon RP (2008) Stereo-selective neuroprotection against stroke with vitamin A derivatives. Brain Res 1241:188–192PubMedGoogle Scholar
  56. 56.
    Malaspina A, Michael-Titus AT (2008) Is the modulation of retinoid and retinoid-associated signaling a future therapeutic strategy in neurological trauma and neurodegeneration? J Neurochem 104:584–595PubMedGoogle Scholar
  57. 57.
    McCaffery P, Drager DC (1994) High level of a retinoic acid-generating dehydrogenase in the meso telencephalic dopamine system. Proc Natl Acad Sci USA 91:7772–7776PubMedGoogle Scholar
  58. 58.
    Nau H, Chahoud I, Dencker L, Lammer RJ, Scott WI (1994) Teratogenicity of vitamin A and retinoids. In: Blomhoff R (ed) Vitamin A in health and disease. Dekker, New York, NY, pp 615–663Google Scholar
  59. 59.
    Satre MA, Ugen KE, Kochhar DM (1992) Developmental changes in endogenous retinoids during pregnancy and embryogenesis in the mouse. Biol Reprod 46:802–810PubMedGoogle Scholar
  60. 60.
    Wagner E, Luo T, Drager UC (2002) Retinoic acid synthesis in the postnatal mouse brain marks distinct developmental stages and functional systems. Cereb Cortex 12:1244–1253PubMedGoogle Scholar
  61. 61.
    Arinami T, Gao M, Hamaguchi H, Toru M (1997) A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia. Hum Mol Genet 6:577–582PubMedGoogle Scholar
  62. 62.
    Balmer JE, Blomhoff R (2002) Gene expression regulation by retinoic acid. J Lipid Res 43:1773–1808PubMedGoogle Scholar
  63. 63.
    Krezel W, Ghyselinck N, Samad TA et al (1998) Impaired locomotion and dopamine signaling in retinoid receptor mutant mice. Science 279:863–867PubMedGoogle Scholar
  64. 64.
    Samad TA, Krezel W, Chambon P, Borrelli E (1997) Regulation of dopaminergic pathways by retinoids: activation of the D2 receptor promoter by members of the retinoic acid receptor-retinoid X receptor family. Proc Natl Acad Sci USA 94:14349–14354PubMedGoogle Scholar
  65. 65.
    Goodman AB (1998) Three independent lines of evidence suggest retinoids as causal to schizophrenia. Proc Natl Acad Sci USA 95:7240–7244PubMedGoogle Scholar
  66. 66.
    Goodman AB (2005) Microarray results suggest altered transport and lowered synthesis of retinoic acid in schizophrenia. Mol Psychiatry 10:620–621PubMedGoogle Scholar
  67. 67.
    Etchamendy N, Enderlin V, Marighetto A, Pallet V, Higueret P, Jaffard R (2003) Vitamin A deficiency and relational memory deficit in adult mice: relationships with changes in brain retinoid signalling. Behav Brain Res 145:37–49PubMedGoogle Scholar
  68. 68.
    Misner DL, Jacobs S, Shimizu Y et al (2001) Vitamin deprivation results in reversible loss of hippocampal long-term synaptic plasticity. Proc Natl Acad Sci USA 98:11714–11719PubMedGoogle Scholar
  69. 69.
    Alfos S, Boucheron C, Pallet V et al (2001) A retinoic acid receptor antagonist suppresses brain retinoic acid receptor overexpression and reverses a working memory deficit induced by chronic ethanol consumption in mice. Alcohol Clin Exp Res 25:1506–1514PubMedGoogle Scholar
  70. 70.
    Corcoran JP, So PL, Maden M (2004) Disruption of the retinoid signalling pathway causes a deposition of amyloid beta in the adult rat brain. Eur J Neurosci 20:896–902PubMedGoogle Scholar
  71. 71.
    Goodman AB, Pardee AB (2003) Evidence for defective retinoid transport and function in late onset Alzheimer’s disease. Proc Natl Acad Sci USA 100:2901–2905PubMedGoogle Scholar
  72. 72.
    Lane MA, Bailey SJ (2005) Role of retinoid signalling in the adult brain. Prog Neurobiol 75:275–293PubMedGoogle Scholar
  73. 73.
    Mey J, McCaffery P (2004) Retinoic acid signaling in the nervous system of adult vertebrates. Neuroscientist 10:409–421PubMedGoogle Scholar
  74. 74.
    Lerner V, Miodownik C, Gibel A et al (2008) Bexarotene as add-on to antipsychotic treatment in schizophrenia patients: a pilot open-label trial. Clin Neuropharmacol 31:25–33PubMedGoogle Scholar
  75. 75.
    Bucci L (1973) Pyridoxine and schizophrenia. Br J Psychiatry 122:240PubMedGoogle Scholar
  76. 76.
    Brooks SC, D’Angelo L, Chalmeta A, Ahern G, Judson JH (1983) An unusual schizophrenic illness responsive to pyridoxine HCl (B6) subsequent to phenothiazine and butyrophenone toxicities. Biol Psychiatry 18:1321–1328PubMedGoogle Scholar
  77. 77.
    Lerner V, Liberman M (1998) Movement disorders and psychotic symptoms treated with pyridoxine: a case report [letter]. J Clin Psychiatry 59:623–624PubMedGoogle Scholar
  78. 78.
    Sandyk R, Pardeshi R (1990) Pyridoxine improves drug-induced parkinsonism and psychosis in a schizophrenic patient. Int J Neurosci 52(3–4):225–232PubMedGoogle Scholar
  79. 79.
    Petrie WM, Ban TA, Ananth JV (1981) The use of nicotinic acid and pyridoxine in the treatment of schizophrenia. Int Pharmacopsychiatry 16:245–250PubMedGoogle Scholar
  80. 80.
    Ananth JV, Ban TA, Lehmann HE (1973) Potentiation of therapeutic effects of nicotinic acid by pyridoxine in chronic schizophrenics. Can Psychiatr Assoc J 18:377–383PubMedGoogle Scholar
  81. 81.
    Ban TA, Lehmann HE, Deutsch M (1977) Negative findings with megavitamins in schizophrenic patients: preliminary report. Commun Psychopharmacol 1:119–122PubMedGoogle Scholar
  82. 82.
    Lerner V, Miodownik C, Kaptsan A, Cohen H, Loewenthal U, Kotler M (2002) Vitamin B6 as add-on treatment in chronic schizophrenic and schizoaffective patients: a double-blind, placebo-controlled study. J Clin Psychiatry 63:54–58PubMedGoogle Scholar
  83. 83.
    Rebec GV, Centore JM, White LK, Alloway KD (1985) Ascorbic acid and the behavioral response to haloperidol: implications for the action of antipsychotic drugs. Science 227:438–440PubMedGoogle Scholar
  84. 84.
    Singh RB, Ghosh S, Niaz MA et al (1995) Dietary intake, plasma levels of antioxidant vitamins, and oxidative stress in relation to coronary artery disease in elderly subjects. Am J Cardiol 76:1233–1238PubMedGoogle Scholar
  85. 85.
    Suboticanec K (1986) Vitamin C status in schizophrenia. Bibl Nutr Dieta 173–181Google Scholar
  86. 86.
    Suboticanec K, Folnegovic-Smalc V, Korbar M, Mestrovic B, Buzina R (1990) Vitamin C status in chronic schizophrenia. Biol Psychiatry 28:959–966PubMedGoogle Scholar
  87. 87.
    Milner G (1963) Ascorbic acid in chronic psychiatric patients: a controlled trial. Br J Psychiatry 109:294–299Google Scholar
  88. 88.
    Beauclair L, Vinogradov S, Riney SJ, Csernansky JG, Hollister LE (1987) An adjunctive role for ascorbic acid in the treatment of schizophrenia? J Clin Psychopharmacol 7:282–283PubMedGoogle Scholar
  89. 89.
    Sandyk R, Kanofsky JD (1993) Vitamin C in the treatment of schizophrenia. Int J Neurosci 68:67–71PubMedGoogle Scholar
  90. 90.
    Smythies JR (1996) The role of ascorbate in brain: therapeutic implications. J R Soc Med 89:241PubMedGoogle Scholar
  91. 91.
    Dakhale GN, Khanzode SD, Khanzode SS, Saoji A (2005) Supplementation of vitamin C with atypical antipsychotics reduces oxidative stress and improves the outcome of schizophrenia. Psychopharmacology (Berl) 182:494–498Google Scholar
  92. 92.
    Arvindakshan M, Ghate M, Ranjekar PK, Evans DR, Mahadik SP (2003) Supplementation with a combination of omega-3 fatty acids and antioxidants (vitamins E and C) improves the outcome of schizophrenia. Schizophr Res 62:195–204PubMedGoogle Scholar
  93. 93.
    McGrath J, Saari K, Hakko H et al (2004) Vitamin D supplementation during the first year of life and risk of schizophrenia: a Finnish birth cohort study. Schizophr Res 67:237–245PubMedGoogle Scholar
  94. 94.
    Becker A, Eyles DW, McGrath JJ, Grecksch G (2005) Transient prenatal vitamin D deficiency is associated with subtle alterations in learning and memory functions in adult rats. Behav Brain Res 161:306–312PubMedGoogle Scholar
  95. 95.
    Yan J, Feng J, Craddock N et al (2005) Vitamin D receptor variants in 192 patients with schizophrenia and other psychiatric diseases. Neurosci Lett 380:37–41PubMedGoogle Scholar
  96. 96.
    McGrath J (1999) Hypothesis: is low prenatal vitamin D a risk-modifying factor for schizophrenia? Schizophr Res 40:173–177PubMedGoogle Scholar
  97. 97.
    Garcion E, Wion-Barbot N, Montero-Menei CN, Berger F, Wion D (2002) New clues about vitamin D functions in the nervous system. Trends Endocrinol Metab 13:100–105PubMedGoogle Scholar
  98. 98.
    Kalueff AV, Eremin KO, Tuohimaa P (2004) Mechanisms of neuroprotective action of vitamin D(3). Biochemistry (Moscow) 69:738–741Google Scholar
  99. 99.
    Kiraly SJ, Kiraly MA, Hawe RD, Makhani N (2006) Vitamin D as a neuroactive substance: review. Sci World J 6:125–139Google Scholar
  100. 100.
    Llewellyn DJ, Langa K, Lang I (2009) Serum 25-Hydroxyvitamin D Concentration and Cognitive Impairment. J Geriatr Psychiatry Neurol 22(3):188–195PubMedGoogle Scholar
  101. 101.
    Wilkins CH, Sheline YI, Roe CM, Birge SJ, Morris JC (2006) Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults. Am J Geriatr Psychiatry 14:1032–1040PubMedGoogle Scholar
  102. 102.
    Armstrong DJ, Meenagh GK, Bickle I, Lee AS, Curran ES, Finch MB (2007) Vitamin D deficiency is associated with anxiety and depression in fibromyalgia. Clin Rheumatol 26:551–554PubMedGoogle Scholar
  103. 103.
    Berk M, Sanders KM, Pasco JA et al (2007) Vitamin D deficiency may play a role in depression. Med Hypotheses 69:1316–1319PubMedGoogle Scholar
  104. 104.
    Grant WB (2009) Does vitamin D reduce the risk of dementia? J Alzheimers Dis 17:151–159PubMedGoogle Scholar
  105. 105.
    Osakada F, Hashino A, Kume T, Katsuki H, Kaneko S, Akaike A (2004) Alpha-tocotrienol provides the most potent neuroprotection among vitamin E analogs on cultured striatal neurons. Neuropharmacology 47:904–915PubMedGoogle Scholar
  106. 106.
    Osakada F, Hashino A, Kume T, Katsuki H, Kaneko S, Akaike A (2003) Neuroprotective effects of alpha-tocopherol on oxidative stress in rat striatal cultures. Eur J Pharmacol 465:15–22PubMedGoogle Scholar
  107. 107.
    Roghani M, Behzadi G (2001) Neuroprotective effect of vitamin E on the early model of Parkinson’s disease in rat: behavioral and histochemical evidence. Brain Res 892:211–217PubMedGoogle Scholar
  108. 108.
    Post A, Rucker M, Ohl F et al (2002) Mechanisms underlying the protective potential of alpha-tocopherol (vitamin E) against haloperidol-associated neurotoxicity. Neuropsychopharmacology 26:397–407PubMedGoogle Scholar
  109. 109.
    D’Souza B, D’Souza V (2003) Oxidative injury and antioxidant vitamins E and C in schizophrenia. Ind J Clin Biochem 18:87–90Google Scholar
  110. 110.
    Bottiglieri T (1996) Folate vitamin B12, and neuropsychiatric disorders. Nutr Rev 54:382–390PubMedGoogle Scholar
  111. 111.
    Bottiglieri T, Hyland K, Laundy M et al (1992) Folate deficiency, biopterin and monoamine metabolism in depression. Psychol Med 22:871–876PubMedGoogle Scholar
  112. 112.
    Hutto BR (1997) Folate and cobalamin in psychiatric illness. Compr Psychiatry 38:305–314PubMedGoogle Scholar
  113. 113.
    Anonymous (1998) Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists’ Collaboration. Br Med J 316:894–898Google Scholar
  114. 114.
    Brouwer IA, van Dusseldorp M, Duran M et al (1999) Low-dose folic acid supplementation does not influence plasma methionine concentrations in young non-pregnant women. Br J Nutr 82:85–89PubMedGoogle Scholar
  115. 115.
    Stabler SP, Marcell PD, Podell ER, Allen RH, Savage DG, Lindenbaum J (1988) Elevation of total homocysteine in the serum of patients with cobalamin or folate deficiency detected by capillary gas chromatography-mass spectrometry. J Clin Invest 81:466–474PubMedGoogle Scholar
  116. 116.
    Akaike A, Tamura Y, Sato Y, Yokota T (1993) Protective effects of a vitamin B12 analog, methylcobalamin, against glutamate cytotoxicity in cultured cortical neurons. Eur J Pharmacol 241:1–6PubMedGoogle Scholar
  117. 117.
    Hector M, Burton JR (1988) What are the psychiatric manifestations of vitamin B12 deficiency? [see comments]. J Am Geriatr Soc 36:1105–1112PubMedGoogle Scholar
  118. 118.
    Silver H (2000) Vitamin B12 levels are low in hospitalized psychiatric patients. Isr J Psychiatry Relat Sci 37:41–45PubMedGoogle Scholar
  119. 119.
    de Carvalho MJ, Guilland JC, Moreau D, Boggio V, Fuchs F (1996) Vitamin status of healthy subjects in Burgundy (France). Ann Nutr Metab 40:24–51PubMedGoogle Scholar
  120. 120.
    Garry PJ, Goodwin JS, Hunt WC (1984) Folate and vitamin B12 status in a healthy elderly population. J Am Geriatr Soc 32:719–726PubMedGoogle Scholar
  121. 121.
    Grinblat J, Marcus DL, Hernandez F, Freedman ML (1986) Folate and vitamin B12 levels in an urban elderly population with chronic diseases. Assessment of two laboratory folate assays: microbiologic and radioassay. J Am Geriatr Soc 34:627–632PubMedGoogle Scholar
  122. 122.
    Beck WS (1991) Neuropsychiatric consequences of cobalamin deficiency. Adv Intern Med 36:33–56PubMedGoogle Scholar
  123. 123.
    Brett AS, Roberts MS (1994) Screening for vitamin B12 deficiency in psychiatric patients. J Gen Intern Med 9:522–524PubMedGoogle Scholar
  124. 124.
    Buchman N, Mendelsson E, Lerner V, Kotler M (1999) Delirium associated with vitamin B12 deficiency after pneumonia. Clin Neuropharmacol 22:356–358PubMedGoogle Scholar
  125. 125.
    Burvill PW, Jackson JM, Smith WG (1969) Psychiatric symptoms due to vitamin B12 deficiency without anaemia. Med J Aust 2:388–390PubMedGoogle Scholar
  126. 126.
    Dommisse J (1991) Subtle vitamin-B12 deficiency and psychiatry: a largely unnoticed but devastating relationship? Med Hypotheses 34:131–140PubMedGoogle Scholar
  127. 127.
    Hansen T, Rafaelson O, Rodbro P (1966) Vitamin B12 deficiency in psychiatry. Lancet 2:965Google Scholar
  128. 128.
    Levitt AJ, Joffe RT (1988) Vitamin B12 in psychotic depression. Br J Psychiatry 153:266–267PubMedGoogle Scholar
  129. 129.
    Lindenbaum J, Healton EB, Savage DG et al (1988) Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. New Engl J Med 318:1720–1728PubMedGoogle Scholar
  130. 130.
    Modell S, Naber D, Muller-Spahn F (1993) [Paranoid psychosis in a patient with hypothyroidism and vitamin B12 deficiency]. Nervenarzt 64:340–342PubMedGoogle Scholar
  131. 131.
    Zucker DK, Livingston RL, Nakra R, Clayton PJ (1981) B12 deficiency and psychiatric disorders: case report and literature review. Biol Psychiatry 16:197–205PubMedGoogle Scholar
  132. 132.
    Lerner V, Kanevsky M, Dwolatzky T, Rouach T, Kamin R, Miodownik C (2006) Vitamin B12 and folate serum levels in newly admitted psychiatric patients. Clin Nutr 25:60–67PubMedGoogle Scholar
  133. 133.
    Regland B, Johansson BV, Gottfries CG (1994) Homocysteinemia and schizophrenia as a case of methylation deficiency. J Neural Transm Gen Sect 98:143–152PubMedGoogle Scholar
  134. 134.
    Carney MW, Sheffield BF (1978) Serum folic acid and B12 in 272 psychiatric in-patients. Psychol Med 8:139–144PubMedGoogle Scholar
  135. 135.
    Godfrey PS, Toone BK, Carney MW et al (1990) Enhancement of recovery from psychiatric illness by methylfolate. Lancet 336:392–395PubMedGoogle Scholar
  136. 136.
    Levine J, Stahl Z, Sela BA et al (2006) Homocysteine-reducing strategies improve symptoms in chronic schizophrenic patients with hyperhomocysteinemia. Biol Psychiatry 60:265–269PubMedGoogle Scholar
  137. 137.
    Freeman MP (2000) Omega-3 fatty acids in psychiatry: a review. Ann Clin Psychiatry 12:159–165PubMedGoogle Scholar
  138. 138.
    Peet M (2008) Omega-3 polyunsaturated fatty acids in the treatment of schizophrenia. Isr J Psychiatry Relat Sci 45:19–25PubMedGoogle Scholar
  139. 139.
    Mellor JE, Laugharne JD, Peet M (1996) Omega-3 fatty acid supplementation in schizophrenic patients. Human Psychopharmacol 11:39–46Google Scholar
  140. 140.
    Peet M, Brind J, Ramchand CN, Shah S, Vankar GK (2001) Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia. Schizophr Res 49:243–251PubMedGoogle Scholar
  141. 141.
    Amminger GP, Schafer MR, Papageorgiou K et al (2010) Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry 67:146–154PubMedGoogle Scholar
  142. 142.
    Berger GE, Proffitt TM, McConchie M et al (2007) Ethyl-eicosapentaenoic acid in first-episode psychosis: a randomized, placebo-controlled trial. J Clin Psychiatry 68:1867–1875PubMedGoogle Scholar
  143. 143.
    Emsley R, Myburgh C, Oosthuizen P, van Rensburg SJ (2002) Randomized, placebo-controlled study of ethyl-eicosapentaenoic acid as supplemental treatment in schizophrenia. Am J Psychiatry 159:1596–1598PubMedGoogle Scholar
  144. 144.
    Peet M, Horrobin DF (2002) A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms. J Psychiatr Res 36:7–18PubMedGoogle Scholar
  145. 145.
    Emsley R, Niehaus DJ, Koen L et al (2006) The effects of eicosapentaenoic acid in tardive dyskinesia: a randomized, placebo-controlled trial. Schizophr Res 84:112–120PubMedGoogle Scholar
  146. 146.
    Fenton WS, Dickerson F, Boronow J, Hibbeln JR, Knable M (2001) A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia. Am J Psychiatry 158:2071–2074PubMedGoogle Scholar
  147. 147.
    Bentsen H (2006) The Norwegian study on the treatment of schizophrenia and schizoaffective disorder with ethyl-EPA and antioxidants. The Second Conference on Brain Phospholipids. Aviemore, ScotlandGoogle Scholar
  148. 148.
    McKenna DJ, Jones K, Hughes K (2001) Efficacy safety, and use of ginkgo biloba in clinical and preclinical applications. Altern Ther Health Med 7(70–86):88–90Google Scholar
  149. 149.
    Smith JV, Luo Y (2004) Studies on molecular mechanisms of Ginkgo biloba extract. Appl Microbiol Biotechnol 64:465–472PubMedGoogle Scholar
  150. 150.
    DeFeudis FV, Drieu K (2000) Ginkgo biloba extract (EGb 761) and CNS functions: basic studies and clinical applications. Curr Drug Targets 1:25–58PubMedGoogle Scholar
  151. 151.
    Ramassamy C, Longpre F, Christen Y (2007) Ginkgo biloba extract (EGb 761) in Alzheimer’s disease: is there any evidence? Curr Alzheimer Res 4:253–262PubMedGoogle Scholar
  152. 152.
    Zhou D, Zhang X, Su J et al (1999) The effects of classic antipsychotic haloperidol plus the extract of ginkgo biloba on superoxide dismutase in patients with chronic refractory schizophrenia. Chin Med J (Engl) 112:1093–1096Google Scholar
  153. 153.
    Atmaca M, Tezcan E, Kuloglu M, Ustundag B, Kirtas O (2005) The effect of extract of ginkgo biloba addition to olanzapine on therapeutic effect and antioxidant enzyme levels in patients with schizophrenia. Psychiatry Clin Neurosci 59:652–656PubMedGoogle Scholar
  154. 154.
    Knable MB (2002) Extract of Ginkgo biloba added to haloperidol was effective for positive symptoms in refractory schizophrenia. Evid Based Ment Health 5:90PubMedGoogle Scholar
  155. 155.
    Zhang XY, Zhou DF, Zhang PY, Wu GY, Su JM, Cao LY (2001) A double-blind, placebo-controlled trial of extract of Ginkgo biloba added to haloperidol in treatment-resistant patients with schizophrenia. J Clin Psychiatry 62:878–883PubMedGoogle Scholar
  156. 156.
    Zhang XY, Zhou DF, Cao LY, Wu GY (2006) The effects of Ginkgo biloba extract added to haloperidol on peripheral T cell subsets in drug-free schizophrenia: a double-blind, placebo-controlled trial. Psychopharmacology (Berl) 188:12–17Google Scholar
  157. 157.
    Ekborg-Ott KH, Taylor A, Armstrong DW (1997) Varietal differences in the total and enantiomeric composition of theanine in tea. J Agric Food Chem 45:353–363Google Scholar
  158. 158.
    Bryan J (2008) Psychological effects of dietary components of tea: caffeine and L-theanine. Nutr Rev 66:82–90PubMedGoogle Scholar
  159. 159.
    Nathan PJ, Lu K, Gray M, Oliver C (2006) The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent. J Herb Pharmacother 6:21–30PubMedGoogle Scholar
  160. 160.
    Yamada T, Terashima T, Okubo T, Juneja LR, Yokogoshi H (2005) Effects of theanine, r-glutamylethylamide, on neurotransmitter release and its relationship with glutamic acid neurotransmission. Nutr Neurosci 8:219–226PubMedGoogle Scholar
  161. 161.
    Egashira N, Hayakawa K, Osajima M et al (2007) Involvement of GABA(A) receptors in the neuroprotective effect of theanine on focal cerebral ischemia in mice. J Pharmacol Sci 105:211–214PubMedGoogle Scholar
  162. 162.
    Kakuda T, Nozawa A, Sugimoto A, Niino H (2002) Inhibition by theanine of binding of [3H]AMPA, [3H]kainate, and [3H]MDL 105,519 to glutamate receptors. Biosci Biotechnol Biochem 66:2683–2686PubMedGoogle Scholar
  163. 163.
    Yokozawa T, Dong E (1997) Influence of green tea and its three major components upon low-density lipoprotein oxidation. Exp Toxicol Pathol 49:329–335PubMedGoogle Scholar
  164. 164.
    Yokogoshi H, Kobayashi M, Mochizuki M, Terashima T (1998) Effect of theanine, r-glutamylethylamide, on brain monoamines and striatal dopamine release in conscious rats. Neurochem Res 23:667–673PubMedGoogle Scholar
  165. 165.
    Terashima T, Takido J, Yokogoshi H (1999) Time-dependent changes of amino acids in the serum, liver, brain and urine of rats administered with theanine. Biosci Biotechnol Biochem 63:615–618PubMedGoogle Scholar
  166. 166.
    Tsuge H, Sano S, Hayakawa T, Kakuda T, Unno T (2003) Theanine gamma-glutamylethylamide, is metabolized by renal phosphate-independent glutaminase. Biochim Biophys Acta 1620:47–53PubMedGoogle Scholar
  167. 167.
    Sadzuka Y, Sugiyama T, Nagamine M, Umegaki K, Sonobe T (2006) Efficacy of theanine is connected with theanine metabolism by any enzyme, not only drug metabolizing enzymes. Food Chem Toxicol 44:286–292PubMedGoogle Scholar
  168. 168.
    Juneja LR, Chu DC, Okubo T, Nagato Y, Yokogoshi H (1999) L-theanine-a unique amino acid of green tea and its relaxation effect in humans. Trends Food Sci Technol 10:199–204Google Scholar
  169. 169.
    Lu K, Gray MA, Oliver C et al (2004) The acute effects of L-theanine in comparison with alprazolam on anticipatory anxiety in humans. Hum Psychopharmacol 19:457–465PubMedGoogle Scholar
  170. 170.
    Kakuda T, Matsuura T, Sagesaka Y, Kawasaki T, Inventors (1996); Product and method for inhibiting caffeine stimulation with theanine. USAGoogle Scholar
  171. 171.
    Kakuda T, Nozawa A, Unno T, Okamura N, Okai O (2000) Inhibiting effects of theanine on caffeine stimulation evaluated by EEG in the rat. Biosci Biotechnol Biochem 64:287–293PubMedGoogle Scholar
  172. 172.
    Kent JM, Mathew SJ, Gorman JM (2002) Molecular targets in the treatment of anxiety. Biol Psychiatry 52:1008–1030PubMedGoogle Scholar
  173. 173.
    Ito K, Nagato Y, Aoi N et al (1998) Effects of L-theanine on the release of alpha-brain waves in human volunteers. Nippon Nogeikagaku Kaishi 72:153–157Google Scholar
  174. 174.
    Yokogoshi H, Mochizuki M, Saitoh K (1998) Theanine-induced reduction of brain serotonin concentration in rats. Biosci Biotechnol Biochem 62:816–817PubMedGoogle Scholar
  175. 175.
    Kobayashi K, Nagato Y, Aoi N et al (1998) Effects of L-theanine on the release of α-brain waves in human volunteers. Nippon Nogeikagaku Kaishi 72:153–157Google Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  1. 1.Department of Psychiatry, Rappaport Faculty of MedicineTechnion – Israel Institute of TechnologyHaifaIsrael
  2. 2.Acute DepartmentSha’ar Menashe Mental Health CenterHaderaIsrael
  3. 3.Division of Psychiatry, Ministry of HealthBe’er Sheva Mental Health CenterBe’er ShevaIsrael
  4. 4.Faculty of Health SciencesBen-Gurion University of the NegevBe’er ShevaIsrael

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