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Is a Neuroprotective Therapy Suitable for Schizophrenia Patients?

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Brain Protection in Schizophrenia, Mood and Cognitive Disorders

Abstract

Schizophrenia is a chronic and disabling mental disorder characterized by positive, negative and mood symptoms, disturbed coping abilities with elevated distress and a significant decline in cognition, quality of life and psychosocial functioning. About one-third of all patients with schizophrenia do not respond adequately to drug treatment. Today neuroscience and clinical research have sufficiently advanced to introduce a novel generation of compounds with neuroprotective properties. The use of neuroprotective agents in schizophrenia is not yet significantly established. An in-depth review of new compounds such as neurosteroids, estrogen, omega-3 fatty acids, S-adenosylmethionine, cannabinoids, piracetam, modafinil, L-theanine, bexarotene with neuroprotective properties is discussed. The mechanisms underlying the neuroprotective effects of these compounds vary and differ from classically defined dopamine and serotonin receptors. This review highlights selective evidence supporting a neuroprotective approach in the search for novel compounds, and suggests future directions for this exciting area. Neuroprotection strategy may be a useful paradigm for treatment of prodromal and first-episode schizophrenia patients and might have a significant impact on the subsequent course and outcome of the illness. The clinical effects of neuroprotective agents clearly merit further investigation in schizophrenia spectrum disorders.

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Abbreviations

AMPA:

alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

BDNF:

Brain-derived neurotrophic factor

CANTAB:

Cambridge Automated Neuropsychological Test Battery

CGI-S:

Clinical Global Impression – Severity scale

CNS:

Central Nervous System

CSF:

Cerebrospinal fluid

Delta9-THC:

Delta(9)-tetrahydrocannabinol

DHA:

docosahexaenoic acid

DHEA:

dehydroepiandrosterone

DHEAS:

dehydroepiandrosterone sulfate

DHEA(S):

DHEA and DHEAS together

DSM-IV:

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition

EPA:

eicosapentaenoic acid

EPS:

Extrapyramidal symptoms

ESRS:

Extrapyramidal Symptom Rating Scale

GABAA :

gamma-aminobutyric acid

HPA:

hypothalamic-pituitary-adrenal axis

HRQL:

the health-related quality of life

ICD-10:

International Classification of Mental and Behavioural Disorders

NMDA:

N-methyl-D-aspartate

PREG:

pregnenolone

PREGS:

pregnenolone sulphate

PREG(S):

PREG and PREGS together

PANSS:

Positive and Negative Syndrome Scale

RARs:

retinoic acid receptors

RXRs:

retinoid X receptors

SANS:

Scale for the Assessment of Negative Symptoms

References

  1. Scolnick EM. Mechanisms of action of medicines for schizophrenia and bipolar illness: status and limitations. Biol Psychiatry. 2006; 59:1039–1045

    Article  PubMed  CAS  Google Scholar 

  2. Buckley PF. Update on the treatment and management of schizophrenia and bipolar disorder. CNS Spectr 2008; 13(2 Suppl 1):1–10; quiz 11–12

    PubMed  Google Scholar 

  3. Agid O, Kapur S, Remington G. Emerging drugs for schizophrenia. Expert Opin Emerg Drugs 2008; 13:479–495

    Article  PubMed  CAS  Google Scholar 

  4. Gründer G, Hippius H, Carlsson A. The ‘atypicality’ of antipsychotics: a concept re-examined and re-defined. Nat Rev Drug Discov 2009; 8:197–202

    Article  PubMed  CAS  Google Scholar 

  5. Lieberman JA, Stroup TS, McEvoy JP, et al. Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353:1209–1223

    Article  PubMed  CAS  Google Scholar 

  6. Ritsner MS. Health-related Quality of Life Impairment in Schizophrenia and Related Disorders as a Target for Neuroprotective Therapy. Int J Neuroprotection Neuroregeneration 2010 (in press)

    Google Scholar 

  7. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Press, Washington, DC; 1994

    Google Scholar 

  8. The ICD-10 Classification of Mental and Behavioural Disorders. Clinical descriptions and diagnostic guidelines. Geneva, World Health Organization; 1992

    Google Scholar 

  9. Ritsner MS, Susser E. Molecular genetics of schizophrenia: focus on symptom dimensions. In: Ritsner MS (ed) The Handbook of Neuropsychiatric Biomarkers, Endophenotypes and Genes. Springer, Vol IV, 2009; pp. 95–124

    Google Scholar 

  10. Musalek M, Scheibenbogen O. From categorical to dimensional diagnostics: deficiency-oriented versus person-centred diagnostics. Eur Arch Psychiatry Clin Neurosci 2008; 258(Suppl 5):18–21

    Article  PubMed  Google Scholar 

  11. van Os J. Is there a continuum of psychotic experiences in the general population? Epidemiol Psichiatr Soc 2003; 12:242–252

    Article  PubMed  Google Scholar 

  12. Lincoln TM. Relevant dimensions of delusions: continuing the continuum versus category debate. Schizophr Res 2007; 93:211–220

    Article  PubMed  Google Scholar 

  13. Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13:261–276

    Article  PubMed  CAS  Google Scholar 

  14. Kay SR, Sevy S. Pyramidical model of schizophrenia. Schizophr Bull 1990; 16:537–545

    Article  PubMed  CAS  Google Scholar 

  15. White L, Harvey PD, Opler L, Lindenmayer JP. Empirical assessment of the factorial structure of clinical symptoms in schizophrenia. A multisite, multimodel evaluation of the factorial structure of the Positive and Negative Syndrome Scale. The PANSS Study Group. Psychopathology 1997; 30:263–274

    Article  PubMed  CAS  Google Scholar 

  16. Shafer A. Meta-analysis of the brief psychiatric rating scale factor structure. Psychol Assess 2005; 17:324–35

    Article  PubMed  Google Scholar 

  17. Andreasen NC. The Scale for the Assessment of Negative Symptoms (SANS): conceptual and theoretical foundations. Br J Psychiatry 1989; Suppl:49–58

    Google Scholar 

  18. Addington D, Addington J, Matincka-Tyndale E. Reliability and validity of a depression rating scale for schizophrenics, Schizophr Res 1992; 6:201–208

    Article  PubMed  CAS  Google Scholar 

  19. Yudofsky SC, Silver JM, Jackson W et al. The Overt Aggression Scale for the objective rating of verbal and physical aggression. Am J Psychiatry 1986; 143:35–39

    PubMed  CAS  Google Scholar 

  20. Kraemer HC, Noda A, O’Hara, R. Categorical versus dimensional approaches to diagnosis: methodological challenges. J Psychiatric Res 2004; 38:17–25

    Article  Google Scholar 

  21. Esterberg ML, Compton MT. The psychosis continuum and categorical versus dimensional diagnostic approaches. Curr Psychiatry Rep 2009; 11:179–184

    Article  PubMed  Google Scholar 

  22. Heinrichs RW. The primacy of cognition in schizophrenia. Am Psychol 2005; 60:229–242

    Article  PubMed  Google Scholar 

  23. Sachs G, Steger-Wuchse D, Kryspin-Exner I, et al. Facial recognition deficits and cognition in schizophrenia. Schizophr Res 2004; 68:27–35

    Article  PubMed  Google Scholar 

  24. Tornatore JB, Hill E, Laboff JA, McGann ME. Self-administered screening for mild cognitive impairment: initial validation of a computerized test battery. J Neuropsychiatry Clin Neurosci 2005; 17:98–105

    Article  PubMed  Google Scholar 

  25. Merrick PI, Secker DI, Fright R, Melding P. The ECO computerized cognitive battery: collection of normative data using elderly New Zealanders. Int Psychogeriatr 2004; 16:93–105

    Article  PubMed  Google Scholar 

  26. Extermann M, Chen H, Booth-Jones M, et al. Pilot testing of the computerized cognitive test Microcog in chemotherapy-treated older cancer patients. Crit Rev Oncol Hematol 2005; 54:137–143

    Article  PubMed  Google Scholar 

  27. Green MF, Nuechterlein KH, Gold JM, et al. Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select cognitive domains and test criteria. Biol Psychiatry 2004; 56:301–307

    Article  PubMed  Google Scholar 

  28. Ritsner MS, Blumenkrantz H, Dubinsky T, Dwolatzky T. The detection of neurocognitive decline in schizophrenia using the Mindstreams Computerized Cognitive Test Battery. Schizophr Res 2006; 82:39–49

    Article  PubMed  Google Scholar 

  29. Robbins TW, James M, Owen AM, Sahakian BJ, McInnes L, Rabbitt P. Cambridge Neuropsychological Test Automated Battery (CANTAB): a factor analytic study of a large sample of normal elderly volunteers. Dementia 1994; 5:266–281

    PubMed  CAS  Google Scholar 

  30. Ritsner MS. Predicting quality of life impairment in chronic schizophrenia from cognitive variables. Qual Life Res 2007; 16:929–937

    Article  PubMed  Google Scholar 

  31. Levaux MN, Potvin S, Sepehry AA, Sablier J, Mendrek A, Stip E. Computerized assessment of cognition in schizophrenia: promises and pitfalls of CANTAB. Eur Psychiatry 2007; 22:104–115

    Article  PubMed  Google Scholar 

  32. Ritsner MS, Awad AG (eds) Quality of Life Impairment in Schizophrenia, Mood and Anxiety Disorders. New Perspectives on Research and Treatment. Springer, 2007; 388 pp

    Google Scholar 

  33. Ritsner MS. The Distress/Protection Vulnerability Model of the quality of life impairment syndrome: current evidence and new directions for research. In: Ritsner MS, Awad AG (eds) Quality of Life Impairment in Schizophrenia, Mood and Anxiety Disorders. New Perspectives on Research and Treatment. Springer, 2007; pp. 3–19

    Google Scholar 

  34. Ritsner M, Modai I, Endicott J, et al. Differences in quality of life domains and psychopathologic and psychosocial factors in psychiatric patients. J Clin Psychiatry 2000; 61:880–889

    Article  PubMed  CAS  Google Scholar 

  35. Ritsner M, Kurs R, Gibel A, et al. Predictors of quality of life in major psychoses: a naturalistic follow-up study. J Clin Psychiatry 2003; 64:308–315

    Article  PubMed  Google Scholar 

  36. Ritsner M, Ponizovsky A, Endicott J, et al. The impact of side-effects of antipsychotic agents on life satisfaction of schizophrenia patients: a naturalistic study. Eur Neuropsychopharmacol 2002; 12:31–38

    Article  PubMed  CAS  Google Scholar 

  37. Ritsner M, Ben-Avi I, Ponizovsky A, et al. Quality of life and coping with schizophrenia symptoms. Qual Life Res 2003; 12:1–9

    Article  PubMed  CAS  Google Scholar 

  38. Ritsner M. Predicting changes in domain-specific quality of life of schizophrenia patients. J Nerv Ment Dis 2003; 191:287–294

    PubMed  Google Scholar 

  39. Ritsner M, Gibel A, Ratner Y. Determinants of changes in perceived quality of life in the course of schizophrenia. Qual Life Res 2006; 15:515–526

    Article  PubMed  Google Scholar 

  40. Ritsner M, Modai I, Kurs R, et al. Subjective quality of life measurements in severe mental health patients: measuring quality of life of psychiatric patients: comparison two questionnaires. Quality Life Res 2002; 11:553–561

    Article  CAS  Google Scholar 

  41. Ponizovsky AM, Grinshpoon A, Levav I, Ritsner MS. Life satisfaction and suicidal attempts among persons with schizophrenia. Comprehensive Psychiatry 2003; 44:442–447

    Article  PubMed  Google Scholar 

  42. Kurs R, Farkas H, Ritsner M. Quality of life and temperament factors in schizophrenia: comparative study of patients, their siblings and controls. Quality Life Res 2005; 14:433–440

    Article  Google Scholar 

  43. Ritsner M, Kurs R, Ponizovsky A, Hadjez J. Perceived quality of life in schizophrenia: relationships to sleep quality. Quality Life Res 2004; 13:783–791

    Article  Google Scholar 

  44. Ritsner M, Perelroyzen G, Kurs R, Ratner Y, Jabarin M, Gibel A. Quality of life outcomes in schizophrenia patients treated with atypical and typical antipsychotic agents: A naturalistic comparative study. Int Clin Psychopharmacol 2004; 24:582–591

    Article  CAS  Google Scholar 

  45. Ritsner M, Kurs R. Quality-of-life impairment in severe mental illness: focus on schizoaffective disorders. In: Murray WH (ed) Schizoaffective Disorder: New Research. NOVA Publishers, NY, 2009; Chapter 3, pp. 69–107

    Google Scholar 

  46. Ritsner MS. Novel neuroprotective agents for schizophrenia: neurosteroids, memantine, bexarotene and L-theanine. In: Lerner V, Miodownik C (eds) New Hope for Mental Disturbances. NOVA Publisher, New-York, 2009, pp. 119–151

    Google Scholar 

  47. Lewis DA, Levitt P. Schizophrenia as a disorder of neurodevelopment. Annu Rev Neurosci 2002; 25:409–432

    Article  PubMed  CAS  Google Scholar 

  48. Rapoport JL, Addington AM, Frangou S, Psych MR. The neurodevelopmental model of schizophrenia: update 2005. Mol Psychiatry 2005; 10:434–449

    Article  PubMed  CAS  Google Scholar 

  49. Lakhan SE, Vieira KF. Schizophrenia pathophysiology: are we any closer to a complete model? Ann Gen Psychiatry 2009; 8:12

    Article  PubMed  Google Scholar 

  50. Ritsner MS (ed) The Handbook of Neuropsychiatric Biomarkers, Endophenotypes and Genes. Springer, Vol. I–IV; 2009

    Google Scholar 

  51. Fatemi SH, Folsom TD. The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophr Bull 2009; 35:528–548

    Article  PubMed  Google Scholar 

  52. Compton MT, Walker EF. Physical manifestations of neurodevelopmental disruption: are minor physical anomalies part of the syndrome of schizophrenia? Schizophr Bull 2009; 35:425–436

    Article  PubMed  Google Scholar 

  53. Wood SJ, Pantelis C, Yung AR, et al. Brain changes during the onset of schizophrenia: implications for neurodevelopmental theories. Med J Aust 2009; 190(4 Suppl):S10–S13

    PubMed  Google Scholar 

  54. Gur RE, Maany V, Mozley PD, et al. Subcortical MRI volumes in neuroleptic-naive and treated patients with schizophrenia. Am J Psychiatry 1998; 155:1711–1717

    PubMed  CAS  Google Scholar 

  55. Zipursky R, Lambe EK, Kapur S, Mikulis DJ. Cerebral gray matter volume deficits in first episode psychosis. Arch Gen Psychiatry 1998; 55:540–546

    Article  PubMed  CAS  Google Scholar 

  56. Arango C, Moreno C, Martínez S, et al. Longitudinal brain changes in early-onset psychosis. Schizophr Bull 2008; 34:341–353

    Article  PubMed  Google Scholar 

  57. Berger GE, Wood S, McGorry PD. Incipient neurovulnerability and neuroprotection in early psychosis. Psychopharmacol Bull 2003; 37:79–101

    PubMed  Google Scholar 

  58. Rapoport JL, Giedd J, Kumra S, et al. Childhood-onset schizophrenia. Progressive ventricular change during adolescence. Arch Gen Psychiatry 1997; 54:897–903

    Article  PubMed  CAS  Google Scholar 

  59. Pantelis C, Velakoulis D, McGorry PD, et al. Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet 2003; 361:281–288

    Article  PubMed  Google Scholar 

  60. Gur RE, Cowell P, Turetsky BI, et al. A follow-up magnetic resonance imaging study of schizophrenia. Relationship of neuroanatomical changes to clinical and neurobehavioral measures. Arch Gen Psychiatry 1998; 55:145–152

    Article  PubMed  CAS  Google Scholar 

  61. Lieberman JA, Perkins D, Belger A, et al. The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches. Biol Psychiatry 2001; 50:884–897

    Article  PubMed  CAS  Google Scholar 

  62. Velakoulis D, Stuart GW, Wood SJ, et al. Selective bilateral hippocampal volume loss in chronic schizophrenia. Biol Psychiatry 2001; 50:531–539

    Article  PubMed  CAS  Google Scholar 

  63. Mathalon DH, Sullivan EV, Lim KO, Pfefferbaum A. Progressive brain volume changes and the clinical course of schizophrenia in men: a longitudinal magnetic resonance imaging study. Arch Gen Psychiatry 2001; 58:148–157

    Article  PubMed  CAS  Google Scholar 

  64. Hulshoff Pol HE, Kahn RS. What happens after the first episode? A review of progressive brain changes in chronically ill patients with schizophrenia. Schizophr Bull 2008; 34:354–366

    Article  PubMed  Google Scholar 

  65. Takahashi T, Wood SJ, Yung AR, et al. Progressive gray matter reduction of the superior temporal gyrus during transition to psychosis. Arch Gen Psychiatry 2009; 66:366–376

    Article  PubMed  Google Scholar 

  66. Thompson PM, Bartzokis G, Hayashi KM, et al. Time-lapse mapping of cortical changes in schizophrenia with different treatments. Cereb Cortex 2009; 19:1107–1123

    Article  PubMed  Google Scholar 

  67. Knoll JLt, Garver DL, Ramberg JE, et al. Heterogeneity of the psychoses: is there a neurodegenerative psychosis? Schizophr Bull 1998; 24:365–379

    Article  PubMed  Google Scholar 

  68. Wright IC, Rabe-Hesketh S, Woodruff PWR, et al. Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry 2000; 157:16–25

    PubMed  CAS  Google Scholar 

  69. Clinton SM, Meador-Woodruff JH. Thalamic dysfunction in schizophrenia: neurochemical, neuropathological, and in vivo imaging abnormalities. Schizophr Res 2004; 69:237–253

    Article  PubMed  Google Scholar 

  70. Ende G, Hubrich P, Walter S, et al. Further evidence for altered cerebellar neuronal integrity in schizophrenia. Am J Psychiatry 2005; 162:790–792

    Article  PubMed  Google Scholar 

  71. Miyamoto S, LaMantia AS, Duncan GE, et al. Recent advances in the neurobiology of schizophrenia. Mol Interv 2003; 3:27–39

    Article  PubMed  Google Scholar 

  72. Keshavan MS, Tandon R, Boutros NN, Nasrallah HA. Schizophrenia, “just the facts”: what we know in 2008 Part 3: neurobiology. Schizophr Res 2008; 106:89–107

    Article  PubMed  Google Scholar 

  73. Ritsner MS, Weizman A (eds) Neuroactive Steroids in Brain Functions, and Mental Health. New Perspectives for Research and Treatment. Springer Springer-Verlag, New York, LLC, 2008; 564 pp

    Google Scholar 

  74. Walker EF, Diforio D. Schizophrenia: a neural diathesis-stress model. Psychol Rev 1997; 104:667–685

    Article  PubMed  CAS  Google Scholar 

  75. Walker E, Mittal V, Tessner K. Stress and the hypothalamic pituitary adrenal axis in the developmental course of schizophrenia. Annu Rev Clin Psychol 2008; 4:189–216

    Article  PubMed  Google Scholar 

  76. Jones SR, Fernyhough C. A new look at the neural diathesis–stress model of schizophrenia: the primacy of social-evaluative and uncontrollable situations. Schizophr Bull 2007; 33:1171–1177

    Article  PubMed  Google Scholar 

  77. Nuechterlein KH, Dawson ME. A heuristic vulnerability/stress model of schizophrenic episodes. Schizophr Bull 1984; 10:300–312

    Article  PubMed  CAS  Google Scholar 

  78. Keshavan MS. Development, disease and degeneration in schizophrenia: a unitary pathophysiological model. J Psychiatr Res 1999; 33:513–521

    Article  PubMed  CAS  Google Scholar 

  79. Bayer TA, Falkai P, Maier W. Genetic and nongenetic vulnerability factors in schizophrenia: The basis of the “two hit hypothesis.” J Psychiatric Res 1999; 33:543–548

    Article  CAS  Google Scholar 

  80. Maynard TM, Sikich L, Lieberman JA, LaMantia AS. Neural development, cell-cell signaling, and the “two-hit” hypothesis of schizophrenia. Schizophr Bull 2001; 27:457–476

    Article  PubMed  CAS  Google Scholar 

  81. McEwen BS. Central effects of stress hormones in health and disease: Understanding the protective and damaging effects of stress and stress mediators. Eur J Pharmacol 2008; 583:174–185

    Article  PubMed  CAS  Google Scholar 

  82. Angelucci F, Brenè S, Mathé AA. BDNF in schizophrenia, depression and corresponding animal models. Mol Psychiatry 2005; 10:345–352

    Article  PubMed  CAS  Google Scholar 

  83. Durany N, Thome J. Neurotrophic factors and the pathophysiology of schizophrenic psychoses. Eur Psychiatry 2004; 19:326–337

    Article  PubMed  Google Scholar 

  84. Velakoulis D, Wood SJ, McGorry PD, Pantelis C. Evidence for progression of brain structural abnormalities in schizophrenia: beyond the neurodevelopmental model. Austr NZ J Psychiatry 2000; 34(Suppl):113–126

    Article  Google Scholar 

  85. Ehrenreich H, Siren AL. Neuroprotection – what does it mean? – What means do we have? Eur Arch Psychiatry Clin Neurosci 2001; 251:149–151

    Article  PubMed  CAS  Google Scholar 

  86. Krebs M, Leopold K, Hinzpeter A, Schaefer M. Neuroprotective agents in schizophrenia and affective disorders. Expert Opin Pharmacother 2006; 7:837–848

    Article  PubMed  CAS  Google Scholar 

  87. Jarskog LF, Lieberman JA. Neuroprotection in schizophrenia. J Clin Psychiatry 2006; 67(9):e09

    Article  PubMed  Google Scholar 

  88. Berger G, Dell’Olio M, Amminger P, et al. Neuroprotection in emerging psychotic disorders. Early Intervention Psychiatry 2007; 1:114–127

    Article  Google Scholar 

  89. Whitcup SM. Clinical trials in neuroprotection. Prog Brain Res 2008; 173:323–335

    Article  PubMed  Google Scholar 

  90. Ehrenreich H, Aust C, Krampe H, et al. Erythropoietin: novel approaches to neuroprotection in human brain disease. Metab Brain Dis 2004; 19:195–206

    Article  PubMed  CAS  Google Scholar 

  91. Niizuma K, Endo H, Chan PH. Oxidative stress and mitochondrial dysfunction as determinants of ischemic neuronal death and survival. J Neurochem 2009; 109 Suppl 1:133–138

    Article  PubMed  CAS  Google Scholar 

  92. Jarskog LF, Glantz LA, Gilmore JH, Lieberman JA. Apoptotic mechanisms in the pathophysiology of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29:846–858

    Article  PubMed  CAS  Google Scholar 

  93. Csernansky JG. Neurodegeneration in schizophrenia: evidence from in vivo neuroimaging studies. Scientific World J 2007; 7:135–143

    Article  Google Scholar 

  94. Jarskog LF, Selinger ES, Lieberman JA, Gilmore JH. Apoptotic proteins in the temporal cortex in schizophrenia: high Bax/Bcl-2 ratio without caspase-3 activation. Am J Psychiatry 2004; 161:109–115

    Article  PubMed  Google Scholar 

  95. Jarskog LF. Apoptosis in schizophrenia: pathophysiologic and therapeutic considerations. Curr Opin Psychiatry 2006; 19:307–312

    Article  PubMed  Google Scholar 

  96. Sies H. Oxidative Stress II: Oxidants and Antioxidants. Academic Press, London; 1991

    Google Scholar 

  97. David S, Warner DS, Sheng H, et al. Oxidants, antioxidants and the ischemic brain. J Exp Biol 2004; 207:3221–3231

    Article  CAS  Google Scholar 

  98. Cadet JL, Kahler LA. Free radical mechanisms in schizophrenia and tardive diskynesia. NeurosciBiobehav Rev 1994; 18:457–467

    CAS  Google Scholar 

  99. Fendri C, Mechri A, Khiari G, Othman A, Kerkeni A, Gaha L. Oxidative stress involvement in schizophrenia pathophysiology: a review. Encephale 2006; 32:244–252. [Article in French]

    Article  PubMed  CAS  Google Scholar 

  100. Mahadik SP, Scheffer RE. Oxidative injury and potential use of antioxidants in schizophrenia. Prostaglandins Leukot Essent Fatty Acids 1996; 55:45–54

    Article  PubMed  CAS  Google Scholar 

  101. Pavlović D, Tamburić V, Stojanović I, et al. Oxidative stress as marker of positive symptoms in schizophrenia. Medicine Biol 2002; 9:157–161

    Google Scholar 

  102. Yao JK, Reddy R, McElhinny LG, van Kammen DP. Reduced status of plasma total antioxidant capacity in schizophrenia. Schizohr Res 1998; 32:1–8

    Article  CAS  Google Scholar 

  103. Vardimon L. Neuroprotection by glutamine synthetase. Isr Med Assoc J 2000; 2(Suppl):46–51

    PubMed  Google Scholar 

  104. Deutsch SI, Rosse RB, Schwartz BL, Mastropaolo J. A revised excitotoxic hypothesis of schizophrenia: therapeutic implications. Clin Neuropharmacol. 2001; 24:43–49

    Article  PubMed  CAS  Google Scholar 

  105. McEwen BS. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev 2007; 87:873–904

    Article  PubMed  Google Scholar 

  106. van Winkel R, Stefanis NC, Myin-Germeys I. Psychosocial stress and psychosis. A review of the neurobiological mechanisms and the evidence for gene-stress interaction. Schizophr Bull 2008; 34:1095–1105

    Article  PubMed  Google Scholar 

  107. Collip D, Myin-Germeys I, Van Os J. Does the concept of “sensitization” provide a plausible mechanism for the putative link between the environment and schizophrenia? Schizophr Bull 2008; 34:220–225

    Article  PubMed  Google Scholar 

  108. Yuii K, Suzuki M, Kurachi M. Stress sensitization in schizophrenia. Ann NY Acad Sci 2007; 1113:276–290

    Article  PubMed  CAS  Google Scholar 

  109. Phillips LJ, McGorry PD, Garner B, et al. Stress, the hippocampus and the hypothalamic-pituitary-adrenal axis: implications for the development of psychotic disorders. Aust NZ J Psychiatry 2006; 40:725–741

    Article  Google Scholar 

  110. De Kloet ER. Hormones and the stressed brain. Ann NY Acad Sci 2004; 1018:1–15

    Article  PubMed  CAS  Google Scholar 

  111. de Kloet ER, Karst H, Joëls M. Corticosteroid hormones in the central stress response: quick-and-slow. Front Neuroendocrinol 2008; 29:268–272

    Article  PubMed  CAS  Google Scholar 

  112. DeRijk R, de Kloet ER. Corticosteroid receptor genetic polymorphisms and stress responsivity. Endocrine 2005; 28:263–270

    Article  PubMed  CAS  Google Scholar 

  113. de Kloet ER, Sibug RM, Helmerhorst FM, Schmidt MV. Stress, genes and the mechanism of programming the brain for later life. Neurosci Biobehav Rev 2005; 29:271–281

    Article  PubMed  CAS  Google Scholar 

  114. Datson NA, Morsink MC, Meijer OC, de Kloet ER. Central corticosteroid actions: Search for gene targets. Eur J Pharmacol 2008; 583:272–289

    Article  PubMed  CAS  Google Scholar 

  115. Lyons DM, Chou Yang, Sawyer-Glover AM, et al. Early Life Stress and Inherited Variation in Monkey Hippocampal Volumes. Arch Gen Psychiatry 2001; 58:1145–1151

    Article  PubMed  CAS  Google Scholar 

  116. Winter H, Irle E. Hippocampal volume in adult burn patients with and without posttraumatic stress disorder. Am J Psychiatry 2004; 161:2194–2200

    Article  PubMed  Google Scholar 

  117. Vythilingam et al. Childhood trauma associated with smaller hippocampal volume in women with major depression. Am J Psychiatry 2002; 159:2072–2080

    Article  PubMed  Google Scholar 

  118. Laruelle M. The role of endogenous sensitization in the pathophysiology of schizophrenia: implications from recent brain imaging studies. Brain Res Brain Res Rev 2000; 31:371–384

    Article  PubMed  CAS  Google Scholar 

  119. Iwazaki T, McGregor IS, Matsumoto I. Protein expression profile in the amygdala of rats with methamphetamine-induced behavioral sensitization. Neurosci Lett 2008; 435:113–119

    Article  PubMed  CAS  Google Scholar 

  120. Myin-Germeys I, Delespaul P, van Os J. Behavioural sensitization to daily life stress in psychosis. Psychol Med 2005; 35:733–741

    Article  PubMed  CAS  Google Scholar 

  121. Ritsner MS, Ratner Y, Gibel A, Weizman R. Positive family history is associated with persistent elevated emotional distress in schizophrenia: evidence from a 16-month follow-up study. Psychiatry Res 2007; 153:217–223

    Article  PubMed  Google Scholar 

  122. Arévalo JC, Wu SH. Neurotrophin signaling: many exciting surprises! Cell Mol Life Sci 2006; 63:1523–1537

    Article  PubMed  CAS  Google Scholar 

  123. Reichardt LF. Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond, B Biol Sci 2006; 361:1545–1564

    Article  CAS  Google Scholar 

  124. Allen SJ, Dawbarn D. Clinical relevance of the neurotrophins and their receptors. Clin. Sci 2006; 110:175–191

    Article  PubMed  CAS  Google Scholar 

  125. Buckley PF, Mahadik S, Pillai A, Terry A Jr. Neurotrophins and schizophrenia. Schizophr Res 2007; 94:1–11

    Article  PubMed  Google Scholar 

  126. Lang UE, Jockers-Scherubl MC, Hellweg R. State of the art of the neurotrophin hypothesis in psychiatric disorders: implications and limitations. J Neural Transm 2004; 111:387–411

    Article  PubMed  CAS  Google Scholar 

  127. Shoval G, Weizman A. The possible role of neurotrophins in the pathogenesis and therapy of schizophrenia. Eur Neuropsychopharmacol 2005; 15:319–329

    Article  PubMed  CAS  Google Scholar 

  128. Moises HW, Zoega T, Gottesman, II. The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia. BMC Psychiatry 2002; 2:8

    Article  PubMed  Google Scholar 

  129. Zimmer DB, Cornwall EH, Landar A, Song W. The S100 protein family: history, function, and expression. Brain Res Bull 1995; 37:417–429

    Article  PubMed  CAS  Google Scholar 

  130. van Beveren NJ, van der Spelt JJ, de Haan L, Fekkes D. Schizophrenia-associated neural growth factors in peripheral blood. A review. Eur Neuropsychopharmacol 2006; 16:469–480

    Article  PubMed  CAS  Google Scholar 

  131. Sen J, Belli A. S100B in neuropathologic states: the CRP of the brain? J Neurosci Res 2007; 85:1373–1380

    Article  PubMed  CAS  Google Scholar 

  132. Rothermundt M, Ponath G, Glaser T, et al. S100B serum levels and long-term improvement of negative symptoms in patients with schizophrenia. Neuropsychopharmacology 2004; 29:1004–1011

    Article  PubMed  CAS  Google Scholar 

  133. Pedersen A, Diedrich M, Kaestner F, et al. Memory impairment correlates with increased S100B serum concentrations in patients with chronic schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:1789–1792

    Article  PubMed  CAS  Google Scholar 

  134. Weickert CS, Hyde TM, Lipska BK, et al. Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia. Mol Psychiatry 2003; 8:592–610

    Article  PubMed  CAS  Google Scholar 

  135. Baulieu EE. Neurosteroids: a novel function of the brain. Psychoneuroendocrinology 1998; 23:963–987

    Article  PubMed  CAS  Google Scholar 

  136. Ritsner MS, Gibel A, Ratner Y, Weizman A. Dehydroepiandrosterone and pregnenolone alterations in schizophrenia. In: Ritsner MS, Weizman A (eds) Neuroactive Steroids in Brain Functions, and Mental Health. New Perspectives for Research and Treatment. Springer Springer-Verlag, New York, LLC, 2008; pp. 251–298

    Google Scholar 

  137. Mellon SH. Neurosteroid regulation of central nervous system development. Pharmacol Ther 2007; 116:107–124

    Article  PubMed  CAS  Google Scholar 

  138. Maninger N, Wolkowitz OM, Reus VI, Epel ES, Mellon SH. Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Front Neuroendocrinol 2009; 30:65–91

    Article  PubMed  CAS  Google Scholar 

  139. Wolf OT, Kirschbaum C. Actions of dehydroepiandrosterone and its sulfate in the central nervous system: effects on cognition and emotion in animals and humans. Brain Res Brain Res Rev 1999; 30:264–288

    Article  PubMed  CAS  Google Scholar 

  140. Gursoy E, Cardounel A, Kalimi M. Pregnenolone protects mouse hippocampal (HT-22) cells against glutamate and amyloid beta protein toxicity. Neurochem Res 2001; 26:15–21

    Article  PubMed  CAS  Google Scholar 

  141. Lhullier FL, Nicolaidis R, Riera NG, et al. Dehydroepiandrosterone increases synaptosomal glutamate release and improves the performance in inhibitory avoidance task. Pharmacol Biochem Behav 2004; 77:601–606

    Article  PubMed  CAS  Google Scholar 

  142. Naert G, Maurice T, Tapia-Arancibia L, Givalois L. Neuroactive steroids modulate HPA axis activity and cerebral brain-derived neurotrophic factor (BDNF) protein levels in adult male rats. Psychoneuroendocrinology 2007; 32:1062–1078

    Article  PubMed  CAS  Google Scholar 

  143. Takahashi H, Nakajima A, Sekihara H. Dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) inhibit the apoptosis in human peripheral blood lymphocytes. J Steroid Biochem Mol Biol 2004; 88:261–264

    Article  PubMed  CAS  Google Scholar 

  144. Charalampopoulos I, Tsatsanis C, Dermitzaki E, et al. Dehydroepiandrosterone and allopregnanolone protect sympathoadrenal medulla cells against apoptosis via antiapoptotic Bcl-2 proteins. Proc Natl Acad Sci USA 2004; 101:8209–8214

    Article  PubMed  CAS  Google Scholar 

  145. Majewska MD. Neurosteroids: endogenous bimodal modulators of the GABAA receptor. Mechanism of action and physiological significance. Prog Neurobiol 1992; 38:379–95

    Article  PubMed  CAS  Google Scholar 

  146. Majewska MD. Neuronal actions of dehydroepiandrosterone. Possible roles in brain development, aging, memory, and affect. Ann NY Acad Sci 1995; 774:111–120

    Article  PubMed  CAS  Google Scholar 

  147. Yapanoglu T, Aksoy Y, Gursan N, Ozbey I, Ziypak T, Calik M. Antiapoptotic effects of dehydroepiandrosterone on testicular torsion/detorsion in rats. Andrologia 2008; 40:38–43

    Article  PubMed  CAS  Google Scholar 

  148. Compagnone NA, Mellon SH. Dehydroepiandrosterone: a potential signaling molecule for neocortical organization during development. Proc Natl Acad Sci USA 1998; 95:4678–4683

    Article  PubMed  CAS  Google Scholar 

  149. Suzuki M, Wright LS, Marwah P, et al. Mitotic and neurogenic effects of dehydroepiandrosterone (DHEA) on human neural stem cell cultures derived from the fetal cortex. Proc Natl Acad Sci USA 2004; 101:3202–3207

    Article  PubMed  CAS  Google Scholar 

  150. Aragno M, Parola S, Brignardello E, et al. Dehydroepiandrosterone prevents oxidative injury induced by transient ischemia/reperfusion in the brain of diabetic rats. Diabetes 2000; 49:1924–1931

    Article  PubMed  CAS  Google Scholar 

  151. Lapchak PA, Araujo DM. Preclinical development of neurosteroids as neuroprotective agents for the treatment of neurodegenerative diseases. Int Rev Neurobiol 2001; 46:379–397

    Article  PubMed  CAS  Google Scholar 

  152. Charalampopoulos I, Alexaki VI, Tsatsanis C, et al. Neurosteroids as endogenous inhibitors of neuronal cell apoptosis in aging. Ann NY Acad Sci 2006; 1088:139–152

    Article  PubMed  CAS  Google Scholar 

  153. Kurata K, Takebayashi M, Morinobu S, Yamawaki S. 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 2004; 311:237–245

    Article  PubMed  CAS  Google Scholar 

  154. Kimonides VG, Khatibi NH, Svendsen CN, et al. Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) protect hippocampal neurons against excitatory amino acid-induced neurotoxicity. Proc Natl Acad Sci USA 1998; 95:1852–1857

    Article  PubMed  CAS  Google Scholar 

  155. Cardounel A, Regelson W, Kalimi M. Dehydroepiandrosterone protects hippocampal neurons against neurotoxin-induced cell death: mechanism of action. Proc Soc Exp Biol Med 1999; 222:145–149

    Article  PubMed  CAS  Google Scholar 

  156. Kimonides VG, Spillantini MG, Sofroniew MV, et al. Dehydroepiandrosterone antagonizes the neurotoxic effects of corticosterone and translocation of stress-activated protein kinase 3 in hippocampal primary cultures. Neuroscience 1999; 89:429–436

    Article  PubMed  CAS  Google Scholar 

  157. Veiga S, Garcia-Segura LM, Azcoitia I. Neuroprotection by the steroids pregnenolone and dehydroepiandrosterone is mediated by the enzyme aromatase. J Neurobiol 2003; 56:398–406

    Article  PubMed  CAS  Google Scholar 

  158. Akan P, Kizildag S, Ormen M, Genc S, Oktem MA, Fadiloglu M. Pregnenolone protects the PC-12 cell line against amyloid beta peptide toxicity but its sulfate ester does not. Chem Biol Interact 2009; 177:65–70

    Article  PubMed  CAS  Google Scholar 

  159. Leskiewicz M, Jantas D, Budziszewska B, Lason W. Excitatory neurosteroids attenuate apoptotic and excitotoxic cell death in primary cortical neurons. J Physiol Pharmacol 2008; 59:457–475

    PubMed  CAS  Google Scholar 

  160. Bologa L, Sharma J, Roberts E. Dehydroepiandrosterone and its sulfated derivative reduce neuronal death and enhance astrocytic differentiation in brain cell cultures. J Neurosci Res 1987; 17:225–234

    Article  PubMed  CAS  Google Scholar 

  161. Karishma KK, Herbert J. Dehydroepiandrosterone (DHEA) stimulates neurogenesis in the hippocampus of the rat, promotes survival of newly formed neurons and prevents corticosterone-induced suppression. Eur J Neurosci 2002; 16:445–453

    Article  PubMed  CAS  Google Scholar 

  162. Bastianetto S, Ramassamy C, Poirier J, Quirion R. Dehydroepiandrosterone (DHEA) protects hippocampal cells from oxidative stress-induced damage. Brain Res Mol Brain Res 1999; 66:35–41

    Article  PubMed  CAS  Google Scholar 

  163. Hu Y, Cardounel A, Gursoy E, Anderson P, Kalimi M. Anti-stress effects of dehydroepiandrosterone: protection of rats against repeated immobilization stress-induced weight loss, glucocorticoid receptor production, and lipid peroxidation. Biochem Pharmacol 2000; 59:753–762

    Article  PubMed  CAS  Google Scholar 

  164. Boudarene M, Legros JJ, Timsit-Berthier M. Study of the stress response: role of anxiety, cortisol and DHEAs. Encephale 2002; 28:139–146

    PubMed  CAS  Google Scholar 

  165. Rasmusson AM, Vythilingam M, Morgan CA 3rd. The neuroendocrinology of posttraumatic stress disorder: new directions. CNS Spectr 2003; 8:651–656, 665–667

    PubMed  Google Scholar 

  166. Debonnel G, Bergeron R, de Montigny C. Potentiation by dehydroepiandrosterone of the neuronal response to N-methyl-D-aspartate in the CA3 region of the rat dorsal hippocampus: an effect mediated via sigma receptors. J Endocrinol 1996; 150(Suppl):S33–S42

    PubMed  CAS  Google Scholar 

  167. Belelli D, Lambert JJ. Neurosteroids: endogenous regulators of the GABA(A) receptor. Nat Rev Neurosci 2005; 6:565–575

    Article  PubMed  CAS  Google Scholar 

  168. Holsboer F, Grasser A, Friess E, Wiedemann K. Steroid effects on central neurons and implications for psychiatric and neurological disorders. Ann NY Acad Sci 1994; 746:345–359

    Article  PubMed  CAS  Google Scholar 

  169. Rupprecht R. The neuropsychopharmacological potential of neuroactive steroids. J Psychiatr Res 1997; 31:297–314

    Article  PubMed  CAS  Google Scholar 

  170. George O, Vallée M, Le Moal M, Mayo W. Neurosteroids and cholinergic systems: implications for sleep and cognitive processes and potential role of age-related changes. Psychopharmacology 2006; 186:402–413

    Article  PubMed  CAS  Google Scholar 

  171. Pérez-Neri I, Montes S, Ojeda-López C, Ramírez-Bermúdez J, Ríos C. Modulation of neurotransmitter systems by dehydroepiandrosterone and dehydroepiandrosterone sulfate: Mechanism of action and relevance to psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:1118–1130

    Article  PubMed  CAS  Google Scholar 

  172. Widstrom RL, Dillon JS. Is there a receptor for dehydroepiandrosterone or dehydroepiandrosterone sulfate? Semin Reprod Med 2004; 22:289–298

    Article  PubMed  CAS  Google Scholar 

  173. Flood JF, Morley JE, Roberts E. Memory-enhancing effects in male mice of pregnenolone and steroids metabolically derived from it. Proc Natl Acad Sci USA 1992; 89:1567–1571

    Article  PubMed  CAS  Google Scholar 

  174. Mathis C, Vogel E, Cagniard B, Criscuolo F, Ungerer A. The neurosteroid pregnenolone sulfate blocks deficits induced by a competitive NMDA antagonist in active avoidance and lever-press learning tasks in mice. Neuropharmacology 1996; 35:1057–1064

    Article  PubMed  CAS  Google Scholar 

  175. Yanase T, Fukahori M, Taniguchi S. Serum dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEA-S) in Alzheimer’s disease and in cerebrovascular dementia. Endocr J 1996; 43:119–123

    Article  PubMed  CAS  Google Scholar 

  176. Silver H, Knoll G, Isakov V, et al. Blood DHEAS concentrations correlate with cognitive function in chronic schizophrenia patients: a pilot study. J Psychiatr Res 2005; 39: 569–575

    Article  PubMed  Google Scholar 

  177. Morrison MF, Redei E, TenHave T. Dehydroepiandrosterone sulfate and psychiatric measures in a frail, elderly residential care population. Biol Psychiatry 2000; 47:144–150

    Article  PubMed  CAS  Google Scholar 

  178. Vallee M, Mayo W, Le Moal M. Role of pregnenolone, dehydroepiandrosterone and their sulfate esters on learning and memory in cognitive aging. Brain Res Brain Res Rev 2001; 37:301–312

    Article  PubMed  CAS  Google Scholar 

  179. Ritsner M, Maayan R, Gibel A, et al. Elevation of the cortisol/dehydroepiandrosterone ratio in schizophrenia patients. Eur Neuropsychopharmacol 2004; 14:267–273

    Article  PubMed  CAS  Google Scholar 

  180. Gallagher P., Ritsner MS. 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. Springer, Vol. III, 2009; pp. 27–45

    Google Scholar 

  181. Roberts E, Fitten LJ. Serum steroid levels in two old men with Alzheimer’s disease (AD) before and after oral administration of dehydroepiandrosterone (DHEA). Pregnenolone synthesis may be ratelimiting in aging. In: Kalimi M, Regelson W (eds) The Biological Role of Dehydroepiandrosterone (DHEA). de Gruyter, Berlin, 1990; pp. 43–63

    Google Scholar 

  182. Ritsner M, Maayan R, Gibel A, Weizman A. Differences in blood pregnenolone and dehydroepiandrosterone levels between schizophrenia patients and healthy subjects. Eur Neuropsychopharmacol 2007; 17:358–365

    Article  PubMed  CAS  Google Scholar 

  183. Semeniuk T, Jhangri GS, Le Melledo JM. Neuroactive steroid levels in patients with generalized anxiety disorder. J Neuropsychiatry Clin Neurosci 2001; 13:396–398

    Article  PubMed  CAS  Google Scholar 

  184. Heydari B, Le Melledo JM. Low pregnenolone sulphate plasma concentrations in patients with generalized social phobia. Psychol Med 2002; 32:929–933

    Article  PubMed  Google Scholar 

  185. Strous RD, Maayan R, Lapidus R, et al. Dehydroepiandrosterone augmentation in the management of negative, depressive, and anxiety symptoms in schizophrenia. Arch Gen Psychiatry 2003; 60:133–141

    Article  PubMed  CAS  Google Scholar 

  186. Nachshoni T, Ebert T, Abramovitch Y, et al. Improvement of extrapyramidal symptoms following dehydroepiandrosterone (DHEA) administration in antipsychotic treated schizophrenia patients: a randomized, double-blind placebo controlled trial. Schizophr Res 2005; 79:251–256

    Article  PubMed  Google Scholar 

  187. Strous RD, Stryjer R, Maayan R, et al. 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 2007; 32:96–105

    Article  PubMed  CAS  Google Scholar 

  188. Ritsner MS, Gibel A, Ratner Y, et al. 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 2006; 26:495–499

    Article  PubMed  CAS  Google Scholar 

  189. Strous RD, Gibel A, Maayan R, Weizman A, Ritsner MS. Hormonal response to dehydroepiandrosterone administration in schizophrenia: findings from a randomized, double-blind, placebo-controlled, crossover study. J Clin Psychopharmacol 2008; 28:456–459

    Article  PubMed  Google Scholar 

  190. Ritsner MS, Strous RD. 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. Journal of Psychiatric Research (2009), doi:10.1016/j.jpsychires.2009.07.002

    Google Scholar 

  191. Ritsner MS. Dehydroepiandrosterone administration in treating medical and neuropsychiatric disorders: high hopes, disappointing results, and topics for future research. In: Ritsner MS, Weizman A (eds) Neuroactive Steroids in Brain Functions, and Mental Health. New Perspectives for Research and Treatment. Springer Springer-Verlag, New York, LLC, 2008; pp. 337–368

    Google Scholar 

  192. Pincus G, Hoagland H. Effects of administered pregnenolone on fatiguing psychomotor performance. J Aviation Med 1944; 15:98–111

    CAS  Google Scholar 

  193. Pincus G, Hoagland H. Effects on industrial production of the administration of pregnenolone to factory workers. J Psychosom Med 1945; 7:342–346

    CAS  Google Scholar 

  194. McGavack T, Chevalley J, Weissberg J. The use of delta 5-pregnenolone in various clinical disorders. J Clin Endocrinol Metab 1951; 11:559–577

    Article  PubMed  CAS  Google Scholar 

  195. Meieran SE, Reus VI, Webster R, Shafton R, Wolkowitz OM. Chronic pregnenolone effects in normal humans: attenuation of benzodiazepine-induced sedation. Psychoneuroendocrinology 2004; 29:486–500

    Article  PubMed  CAS  Google Scholar 

  196. Ritsner MS, Gibel A, Shleifer T, et al. Pregnenolone and dehydroepiandrosterone as an adjunctive treatment in schizophrenia: an 8-week, double-blind, randomized, controlled, two-center, parallel-group trial. J Clin Psychiatry 2010 (in press)

    Google Scholar 

  197. Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA. Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 1996; 93: 5925–5930

    Article  PubMed  CAS  Google Scholar 

  198. Ogawa S, Inoue S, Watanabe T, Hiroi H, Orimo A, Hosoi T, Ouchi Y, Muramatsu M. The complete primary structure of human estrogen receptor beta (hER beta) and its heterodimerization with ER alpha in vivo and in vitro. Biochem Biophys Res Commun 1998; 243:122–126

    Article  PubMed  CAS  Google Scholar 

  199. Green PS, Simpkins JW. Neuroprotective effects of estrogens: potential mechanisms of action. Int J Dev Neurosci 2000; 18:347–358

    Article  PubMed  CAS  Google Scholar 

  200. Lee SJ, McEwen BS. Neurotrophic and neuroprotective actions of estrogens and their therapeutic implications. Annu Rev Pharmacol Toxicol 2001; 41:569–591

    Article  PubMed  CAS  Google Scholar 

  201. Mendez P, Azcoitia I, Garcia-Segura LM. Interdependence of oestrogen and insulin-like growth factor-I in the brain: potential for analysing neuroprotective mechanisms J Endocrinol 2005; 185:11–17

    CAS  Google Scholar 

  202. Wise PM, Dubal DB, Wilson ME, et al. Estradiol is a protective factor in the adult and aging brain: understanding of mechanisms derived from in vivoand in vitrostudies. Brain Res Rev 2001; 37:313–319

    Article  PubMed  CAS  Google Scholar 

  203. Wise PM, Dubal DB, Rau SW, Brown CM, Suzuki S. Are Estrogens protective or risk factors in brain injury and neurodegeneration? Reevaluation after the women’s health initiative. Endocrine Rev 2005; 26:308–312

    Article  CAS  Google Scholar 

  204. Simpkins JW, Green PS, Gridley JS, Monck EK. Neuroprotective effects of estrogens. In: Bellino FL (ed) Biology of Menopause. Springer-Verlag, New York, 2000; pp.103–111

    Chapter  Google Scholar 

  205. Brann DW, Dhandapani K, Wakade C, Mahesh VB, Khan MM. Neurotrophic and neuroprotective actions of estrogen: basic mechanisms and clinical implications. Steroids 2007; 72:381–405

    Article  PubMed  CAS  Google Scholar 

  206. Singh M, Dykens JA, Simpkins JW. Novel mechanisms for estrogen-induced neuroprotection. Exp Biol Med (Maywood) 2006; 231:514–521

    CAS  Google Scholar 

  207. Salokangas RK. Gender and the use of neuroleptics in schizophrenia. Further testing of the oestrogen hypothesis. Schizophr Res 1995; 16:7–16

    Article  PubMed  CAS  Google Scholar 

  208. Huber TJ, Tettenborn C, Leifke E, Emrich HM: Sex hormones in psychotic men. Psychoneuroendocrinology 2005, 30:111–114.

    Article  PubMed  CAS  Google Scholar 

  209. Bergemann N, Mundt C, Parzer P, et al. Estrogen as an adjuvant therapy to antipsychotics does not prevent relapse in women suffering from schizophrenia: results of a placebo-controlled double-blind study. Schizophr Res 2005; 74:125–134

    Article  PubMed  Google Scholar 

  210. Mortimer AM. Relationship between estrogen and schizophrenia. Expert Rev Neurother 2007; 7:45–55

    Article  PubMed  CAS  Google Scholar 

  211. Kulkarni J. Oestrogen – a new treatment approach for schizophrenia? Med J Aust 2009; 190(4 Suppl):S37–S38

    PubMed  Google Scholar 

  212. Seeman MV, Lang M. The role of estrogens in schizophrenia gender differences. Schizophr Bull 1990; 16:185–194

    Article  PubMed  CAS  Google Scholar 

  213. Riecher-Rössler A. Estrogens and schizophrenia. In: Bergemann N, Riecher-Rössler A (eds) Oestrogen Effects in Psychiatric Disorders. Springer, Wien, 2005; pp. 31–52

    Chapter  Google Scholar 

  214. Cantoni GL. S-adenosylmethionine: a new intermediate formed enzymatically from L-methionine and adenosine-triphosphate. J Biol Chem 1953; 204:403–416

    CAS  Google Scholar 

  215. Fetrow CW, Avila JR. Efficacy of the dietary supplement S-adenosyl-L-methionine. Ann Pharmacother 2001; 35:1414–1425

    Article  PubMed  CAS  Google Scholar 

  216. Surtees R, Leonard J, Austin S. Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway. Lancet 1991; 338:1550–1554

    Article  PubMed  CAS  Google Scholar 

  217. Bell KM, Potkin SG, Carreon D, Plon L. S-adenosylmethionine blood levels in major depression: changes with drug treatment. Acta Neurol Scand Suppl 1994; 154:15–18

    Article  PubMed  CAS  Google Scholar 

  218. Stramentinoli G, Gualano M, Galli-Kienle M, Intestinal absorption of S-adenosyl-L-methionine. J Pharmacol Exp Ther 1979; 209:323–326

    PubMed  CAS  Google Scholar 

  219. Stramentinoli G. Pharmacologic aspects of S-adenosylmethionine. Pharmacokinetics and pharmacodynamics. Am J Med 1987; 83:35–42

    Article  PubMed  CAS  Google Scholar 

  220. Bottiglieri T, Godfrey P, Flynn T, et al. Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine. J Neurol Neurosurg Psychiatry 1990; 53:1096–1098

    Article  PubMed  CAS  Google Scholar 

  221. Malakar D, Dey A, Ghosh AK. Protective role of S-adenosyl-L-methionine against hydrochloric acid stress in Saccharomyces cerevisiae. Biochim Biophys Acta 2006; 1760:1298–1303

    Article  PubMed  CAS  Google Scholar 

  222. Malakar D, Dey A, Basu A, Ghosh AK. Antiapoptotic role of S-adenosyl-l-methionine against hydrochloric acid induced cell death in Saccharomyces cerevisiae. Biochim Biophys Acta 2008; 1780:937–947

    Article  PubMed  CAS  Google Scholar 

  223. James SJ, Cutler P, Melnyk S, et al. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am J Clin Nutr 2004; 80: 1611–1617

    PubMed  CAS  Google Scholar 

  224. Stramentinoli G, Gualano M, Catto E, Algeri S.Tissue levels of S-adenosylmethionine in aging rats. J Gerontol 1977; 32:392–394

    Article  PubMed  CAS  Google Scholar 

  225. Laudanno OM. Cytoprotective effect of S-adenosylmethionine compared with that of misoprostol against ethanol-, aspirin-, and stress-induced gastric damage. Am J Med 1987; 83:43–47

    Article  PubMed  CAS  Google Scholar 

  226. Mato JM, Camara J, Fernandez de Paz J, et al. S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial. J Hepatol 1999; 30:1081–1089

    Article  PubMed  CAS  Google Scholar 

  227. Gatto G, Caleri D, Michelacci S, Sicuteri F. Analgesizing effect of a methyl donor (S-adenosylmethionine) in migraine: an open clinical trial. Int J Clin Pharmacol Res 1986; 6:15–17

    PubMed  CAS  Google Scholar 

  228. Morrison LD, Smith DD, Kish SJ. Brain S-adenosylmethionine levels are severely decreased in Alzheimer’s disease. J Neurochem 1996; 67:1328–1331

    Article  PubMed  CAS  Google Scholar 

  229. Friedel HA, Goa KL, Benfield P. S-adenosyl-L-methionine. A review of its pharmacological properties and therapeutic potential in liver dysfunction and affective disorders in relation to its physiological role in cell metabolism. Drugs 1089; 38:389–416

    Google Scholar 

  230. Papakostas GI, Alpert JE, Fava M. S-adenosyl-methionine in depression: a comprehensive review of the literature. Curr Psychiatry Rep 2003; 5:460–466

    Article  PubMed  Google Scholar 

  231. Strous RD, Ritsner MS, Adler S, et al. Improvement of aggressive behavior and quality of life impairment following S-adenosyl-methionine (SAM-e) augmentation in schizophrenia. Eur Neuropsychopharmacol 2009; 19:14–22

    Article  PubMed  CAS  Google Scholar 

  232. Ullrich O, Merker K, Timm J, Tauber S. Immune control by endocannabinoids – new mechanisms of neuroprotection? J Neuroimmunol 2007; 184:127–135

    Article  PubMed  CAS  Google Scholar 

  233. Roser P, Vollenweider FX, Kawohl W. Potential antipsychotic properties of central cannabinoid (CB(1)) receptor antagonists. World J Biol Psychiatry 2008; 7:1–12

    Google Scholar 

  234. Grotenhermen F. Cannabinoids. Curr Drug Targets CNS Neurol Disord 2005; 4:507–530

    Article  PubMed  CAS  Google Scholar 

  235. Moreira FA, Aguiar DC, Guimarães FS. Anxiolytic-like effect of cannabidiol in the rat Vogel conflict test. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30:1466–1471

    Article  PubMed  CAS  Google Scholar 

  236. Zuardi AW, Crippa JA, Hallak JE, et al. Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res 2006; 39:421–429

    Article  PubMed  CAS  Google Scholar 

  237. de Lago E, Fernández-Ruiz J. Cannabinoids and neuroprotection in motor-related disorders. CNS Neurol Disord Drug Targets 2007; 6:377–387

    Article  PubMed  Google Scholar 

  238. Davies SN, Pertwee RG, Riedel G. Functions of cannabinoid receptors in the hippocampus. Neuropharmacology 2002; 42:993–1007

    Article  PubMed  CAS  Google Scholar 

  239. Fride E, Shohami E. The endocannabinoid system: function in survival of the embryo, the newborn and the neuron. Neuroreport 2002; 13:1833–1841

    Article  PubMed  CAS  Google Scholar 

  240. Pryce G, Ahmed Z, Hankey DJ, et al. Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain 2003; 126:2191–2202

    Article  PubMed  Google Scholar 

  241. van der Stelt M, Veldhuis WB, Maccarrone M, et al. Acute neuronal injury, excitotoxicity, and the endocannabinoid system. Mol Neurobiol 2002; 26:317–346

    Article  PubMed  Google Scholar 

  242. Zhuang SY, Bridges D, Grigorenko E, et al. Cannabinoids produce neuroprotection by reducing intracellular calcium release from ryanodine-sensitive stores. Neuropharmacology 2005; 48:1086–1096

    Article  PubMed  CAS  Google Scholar 

  243. D’Souza DC, Pittman B, Perry E, Simen A. Preliminary evidence of cannabinoid effects on brain-derived neurotrophic factor (BDNF) levels in humans. Psychopharmacology (Berl) 2009; 202:569–578

    Article  CAS  Google Scholar 

  244. Bhattacharyya S, Fusar-Poli P, Borgwardt S, et al. Modulation of mediotemporal and ventrostriatal function in humans by Delta9-tetrahydrocannabinol: a neural basis for the effects of Cannabis sativa on learning and psychosis. Arch Gen Psychiatry 2009; 66:442–451

    Article  PubMed  CAS  Google Scholar 

  245. Semple DM, McIntosh AM, Lawrie SM. Cannabis as a risk factor for psychosis: systematic review. J Psychopharmacol 2005; 19:187–194

    Article  PubMed  Google Scholar 

  246. Ben Amar M, Potvin S. Cannabis and psychosis: what is the link? J Psychoactive Drugs 2007; 39:131–142

    Article  PubMed  Google Scholar 

  247. Cohen M, Solowij N, Carr V. Cannabis, cannabinoids and schizophrenia: integration of the evidence. Aust NZ J Psychiatry 2008; 42:357–368

    Article  Google Scholar 

  248. Rathbone J, Variend H, Mehta H. Cannabis and schizophrenia. Cochrane Database Syst Rev 2008; (3):CD004837

    Google Scholar 

  249. Sewell RA, Ranganathan M, D’Souza DC. Cannabinoids and psychosis. Int Rev Psychiatry 2009; 21:152–162

    Article  PubMed  Google Scholar 

  250. D’Souza DC, Abi-Saab WM, Madonick S, et al. Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction. Biol Psychiatry 2005; 57:594–608

    Article  PubMed  CAS  Google Scholar 

  251. Schwarcz G, Karajgi B, McCarthy R. Synthetic delta-9-tetrahydrocannabinol (dronabinol) can improve the symptoms of schizophrenia. J Clin Psychopharmacol 2009; 29:255–258

    Article  PubMed  CAS  Google Scholar 

  252. Moore TH, Zammit S, Lingford-Hughes A, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet 2007; 370:319–328

    Article  PubMed  Google Scholar 

  253. Zammit S, Moore TH, Lingford-Hughes A, et al. Effects of cannabis use on outcomes of psychotic disorders: systematic review. Br J Psychiatry 2008; 193:357–363

    Article  PubMed  Google Scholar 

  254. Müller-Vahl KR, Emrich HM. Cannabis and schizophrenia: towards a cannabinoid hypothesis of schizophrenia. Expert Rev Neurother 2008; 8:1037–1048

    Article  PubMed  Google Scholar 

  255. Pertwee RG. Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br J Pharmacol 2009 Feb; 156(3):397–411

    Article  PubMed  CAS  Google Scholar 

  256. Peet M, Stokes C. Omega-3 fatty acids in the treatment of psychiatric disorders. Drugs 2005; 65:1051–1059

    Article  PubMed  CAS  Google Scholar 

  257. Moreira JD, Knorr L, Thomazi AP, et al. Dietary omega-3 fatty acids attenuate cellular damage after a hippocampal ischemic insult in adult rats. J Nutr Biochem 2009 May 1. [Epub ahead of print]

    Google Scholar 

  258. Kaur P, Heggland I, Aschner M, Syversen T. Docosahexaenoic acid may act as a neuroprotector for methylmercury-induced neurotoxicity in primary neural cell cultures. Neurotoxicology 2008; 29:978–987

    Article  PubMed  CAS  Google Scholar 

  259. Berman DR, Mozurkewich E, Liu Y, Barks J. Docosahexaenoic acid pretreatment confers neuroprotection in a rat model of perinatal cerebral hypoxia-ischemia. Am J Obstet Gynecol 2009; 200:305.e1–6

    Article  CAS  Google Scholar 

  260. Fenton WS, Dickerson F, Boronow J, Hibbeln JR, Knable M. A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia. Am J Psychiatry 2001; 158:2071–2074

    Article  PubMed  CAS  Google Scholar 

  261. Freeman MP, Hibbeln JR, Wisner KL, et al. Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry. J Clin Psychiatry 2006; 67:1954–1967

    Article  PubMed  CAS  Google Scholar 

  262. Peet M. Omega-3 polyunsaturated fatty acids in the treatment of schizophrenia. Isr J Psychiatry Relat Sci 2008; 45:19–25

    PubMed  Google Scholar 

  263. Emsley R, Niehaus DJ, Oosthuizen PP, et al. Safety of the omega-3 fatty acid, eicosapentaenoic acid (EPA) in psychiatric patients: results from a randomized, placebo-controlled trial. Psychiatry Res 2008; 161:284–291

    Article  PubMed  CAS  Google Scholar 

  264. Mindus P, Cronholm B, Levander SE, Schalling D. Piracetam-induced improvement of mental performance. A controlled study on normally aging individuals. Acta Psychiatr Scand 1976; 54:150–160

    Article  PubMed  CAS  Google Scholar 

  265. Deberdt W. Interaction between psychological and pharmacological treatment in cognitive impairment. Life Sci 1994; 55:2057–2066

    Article  PubMed  CAS  Google Scholar 

  266. Giurgea C. Piracetam: nootropic pharmacology of neurointegrative activity. Curr Dev Psychopharmacol 1976; 3:223–723

    Google Scholar 

  267. O’Neill MJ, Bleakman D, Zimmerman DM, Nisenbaum ES. AMPA receptor potentiators for the treatment of CNS disorders. Curr Drug Targets CNS Neurol Disord 2004; 3:181–194

    Article  PubMed  Google Scholar 

  268. Taupin P. Nootropic agents stimulate neurogenesis. Expert Opin Ther Pat 2009; 19: 727–730

    Article  PubMed  CAS  Google Scholar 

  269. Muller WE, Eckert GP, Eckert A. Piracetam: novelty in a unique mode of action. Pharmacopsychiatry 1999; 32 Suppl 1:2–9

    Article  PubMed  CAS  Google Scholar 

  270. Cohen S, Mueller W. Interaction of piracetam with several neurotransmitter receptors in central nervous system – relative specificity for 3H-glutamate sites. Arzneimittelforschung 1985; 35:1350–1352

    Google Scholar 

  271. Muller WE, Koch S, Scheuer K, Rostock A, Bartsch R. Effects of piracetam on membrane fluidity in the aged mouse, rat, and human brain. Biochem Pharmacol 1997; 53:135–140

    Article  PubMed  CAS  Google Scholar 

  272. Gouliaev AH, Senning A. Piracetam and other structurally related nootropics. Brain Res Brain Res Rev 1994; 19:180–222

    Article  PubMed  CAS  Google Scholar 

  273. Libov I, Miodownik C, Bersudsky Y, Dwolatzky T, Lerner V. Efficacy of piracetam in the treatment of tardive dyskinesia in schizophrenic patients: a randomized, double-blind, placebo-controlled crossover study. J Clin Psychiatry 2007; 68:1031–1037

    Article  PubMed  CAS  Google Scholar 

  274. van Vliet SA, Blezer EL, Jongsma MJ, et al. Exploring the neuroprotective effects of modafinil in a marmoset Parkinson model with immunohistochemistry, magnetic resonance imaging and spectroscopy. Brain Res 2008; 1189:219–228

    Article  PubMed  CAS  Google Scholar 

  275. Minzenberg MJ, Carter CS. Modafinil: a review of neurochemical actions and effects on cognition. Neuropsychopharmacology 2008; 33:1477–1502

    Article  PubMed  CAS  Google Scholar 

  276. Turner DC, Clark L, Pomarol-Clotet E, et al. Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia. Neuropsychopharmacology 2004; 29:1363–1373

    Article  PubMed  CAS  Google Scholar 

  277. Sevy S, Rosenthal MH, Alvir J, et al. Double-blind, placebo-controlled study of modafinil for fatigue and cognition in schizophrenia patients treated with psychotropic medications. J Clin Psychiatry 2005; 66:839–843

    Article  PubMed  CAS  Google Scholar 

  278. Saavedra-Velez C, Yusim A, Anbarasan D, Lindenmayer JP. Modafinil as an adjunctive treatment of sedation, negative symptoms, and cognition in schizophrenia: a critical review. J Clin Psychiatry 2009; 70:104–112

    Article  PubMed  CAS  Google Scholar 

  279. Ekborg-Ott KH, Taylor A, Armstrong DW. Varietal differences in the total and enantiomeric composition of theanine in tea. J Agric Food Chem 1997; 45:353–363

    Article  CAS  Google Scholar 

  280. Unno T, Suzuki Y, Kakuda T, et al. Metabolism of theanine, gamma-glutamylethylamide, in rats. J Agric Food Chem 1999; 47:1593–1596

    Article  PubMed  CAS  Google Scholar 

  281. Bukowski JF, Morita CT, Brenner MB. Human gamma delta T cells recognize alkylamines derived from microbes, edible plants, and tea: implications for innate immunity. Immunity 1999; 11:57–65

    Article  PubMed  CAS  Google Scholar 

  282. Terashima T, Takido J, Yokogoshi H. Time-dependent changes of amino acids in the serum, liver, brain and urine of rats administered with theanine. Biosci Biotechnol Biochem 1999; 63:615–618

    Article  PubMed  CAS  Google Scholar 

  283. Kakuda T, Nozawa A, Unno T, Okamura N, Okai O. Inhibiting effects of theanine on caffeine stimulation evaluated by EEG in the rat. Biosci Biotechnol Biochem 2000; 64:287–293

    Article  PubMed  CAS  Google Scholar 

  284. Lu K, Gray MA, Oliver C, et al. The acute effects of L-theanine in comparison with alprazolam on anticipatory anxiety in humans. Hum Psychopharmacol 2004; 19:457–465

    Article  PubMed  CAS  Google Scholar 

  285. Sadzuka Y, Sugiyama T, Miyagishima A, et al. The effects of theanine, as a novel biochemical modulator, on the antitumor activity of adriamycin. Cancer Lett 1996; 105:203–209

    Article  PubMed  CAS  Google Scholar 

  286. Yokozawa T, Dong E. Influence of green tea and its three major components upon low-density lipoprotein oxidation. Exp Toxicol Pathol 1997; 49:329–335

    Article  PubMed  CAS  Google Scholar 

  287. Sugiyama T, Sadzuka Y. Theanine, a specific glutamate derivative in green tea, reduces the adverse reactions of doxorubicin by changing the glutathione level. Cancer Lett 2004; 212:177–184

    Article  PubMed  CAS  Google Scholar 

  288. Kakuda T, Nozawa A, Sugimoto A, Niino H. Inhibition by theanine of binding of [3H]AMPA, [3H]kainate, and [3H]MDL 105,519 to glutamate receptors. Biosci Biotechnol Biochem 2002; 66:2683–2686

    Article  PubMed  CAS  Google Scholar 

  289. Nagasawa K, Aoki H, Yasuda E, Nagai K, Shimohama S, Fujimoto S. Possible involvement of group I mGluRs in neuroprotective effect of theanine. Biochem Biophys Res Commun 2004; 320:116–122

    Article  PubMed  CAS  Google Scholar 

  290. Mason R. 200 mg of Zen. L-theanine boosts alpha waves, promotes alert relaxation. Alternative & Complementary Therapies 2001; 7:91–95

    Article  Google Scholar 

  291. Kimura R, Murata T. Influence of alkylamides of glutamic acid and related compounds on the central nervous system. II. Syntheses of amides of gutamic acid and related compounds, and their effects on the central nervous system. Chem Pharm Bull (Tokyo) 1971; 19:1301–7

    Article  CAS  Google Scholar 

  292. Juneja LR, Chu DC, Okubo T, et al. L-theanine-a unique amino acid of green tea and its relaxation effect in humans. Trends Food Sci Technol 1999; 10:199–204

    Article  CAS  Google Scholar 

  293. Kakuda T, Matsuura T, Sagesaka Y, Kawasaki T. Product and method for inhibiting caffeine stimulation with theanine. vol 5,501,866. USA, 1996

    Google Scholar 

  294. Kent JM, Mathew SJ, Gorman JM. Molecular targets in the treatment of anxiety. Biol Psychiatry 2002; 52:1008–1030

    Article  PubMed  CAS  Google Scholar 

  295. Ito K, Nagato Y, Aoi N, et al. Effects of L-theanine on the release of alpha-brain waves in human volunteers. Nippon Nogeikagaku Kaishi 1998; 72:153–157

    Article  Google Scholar 

  296. Yokogoshi H, Kobayashi M, Mochizuki M, Terashima T. Effect of theanine, r-glutamylethylamide, on brain monoamines and striatal dopamine release in conscious rats. Neurochem Res 1998; 23:667–673

    Article  PubMed  CAS  Google Scholar 

  297. Yokogoshi H, Mochizuki M, Saitoh K. Theanine-induced reduction of brain serotonin concentration in rats. Biosci Biotechnol Biochem 1998; 62:816–817

    Article  PubMed  CAS  Google Scholar 

  298. Kobayashi K, Nagato Y, Aoi N, Juneja LR, Kim M, et al. Effects of L-theanine on the release of α-brain waves in human volunteers. Nippon Nogeikagaku Kaishi 1998; 72:153–157

    Article  CAS  Google Scholar 

  299. Ritsner MS, Miodownik C, Ratner Y, et al. L-theanine relieves positive, activation, and anxiety symptoms in patients with schizophrenia and schizoaffective disorders: an 8-week, randomized, double-blind, placebo-controlled, two-center study. J Clin Psychiatry 2010 (in press)

    Google Scholar 

  300. Sporn MB, Roberts AB. Role of retinoids in differentiation and carcinogenesis. J Natl Cancer Inst 1984; 73:1381–1387

    PubMed  CAS  Google Scholar 

  301. Tafti M, Ghyselinck NB. Functional implication of the vitamin A signaling pathway in the brain. Arch Neurol 2007; 64:1706–1711

    Article  PubMed  Google Scholar 

  302. Oridate N, Lotan D, Xu XC, Hong WK, Lotan R. Differential induction of apoptosis by all-trans-retinoic acid and N-(4-hydroxyphenyl)retinamide in human head and neck squamous cell carcinoma cell lines. Clin Cancer Res 1996; 2:855–863

    PubMed  CAS  Google Scholar 

  303. Sarah J. Bailey SJ, McCaffery PJ. Retinoic acid signalling in neuropsychiatric disease: possible markers and treatment agents. In: Ritsner MS (ed) The Handbook of Neuropsychiatric Biomarkers, Endophenotypes and Genes. Springer, Vol III, 2009; pp. 171–189

    Google Scholar 

  304. Gorgun G, Foss F. Immunomodulatory effects of RXR rexinoids: modulation of high-affinity IL-2R expression enhances susceptibility to denileukin diftitox. Blood 2002; 100:1399–1403

    Article  PubMed  CAS  Google Scholar 

  305. McCaffery P, Drager UC. High levels of a retinoic acid-generating dehydrogenase in the meso-telencephalic dopamine system. Proc Natl Acad Sci USA 1994; 91:7772–7776

    Article  PubMed  CAS  Google Scholar 

  306. Wagner E, Luo T, Drager UC. Retinoic acid synthesis in the postnatal mouse brain marks distinct developmental stages and functional systems. Cereb Cortex 2002; 12:1244–1253

    Article  PubMed  Google Scholar 

  307. Arinami T, Gao M, Hamaguchi H, Toru M. A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia. Hum Mol Genet 1997; 6:577–582

    Article  PubMed  CAS  Google Scholar 

  308. Balmer JE, Blomhoff R. Gene expression regulation by retinoic acid. J Lipid Res 2002; 43:1773–1808

    Article  PubMed  CAS  Google Scholar 

  309. Krezel W, Ghyselinck N, Samad TA, Dupe V, Kastner P, Borrelli E, Chambon P. Impaired locomotion and dopamine signaling in retinoid receptor mutant mice. Science 1998; 279:863–867

    Article  PubMed  CAS  Google Scholar 

  310. Palha JA, Goodman AB. Thyroid hormones and retinoids: a possible link between genes and environment in schizophrenia. Brain Res Rev 2006; 51:61–71

    Article  PubMed  CAS  Google Scholar 

  311. Goodman AB. Three independent lines of evidence suggest retinoids as causal to schizophrenia. Proc Natl Acad Sci USA 1998; 95:7240–7244

    Article  PubMed  CAS  Google Scholar 

  312. Goodman AB. Chromosomal locations and modes of action of genes of the retinoid (vitamin A) system support their involvement in the etiology of schizophrenia. Am J Med Genet 1995; 60:335–48

    Article  PubMed  CAS  Google Scholar 

  313. Etchamendy N, Enderlin V, Marighetto A, et al. Vitamin A deficiency and relational memory deficit in adult mice: relationships with changes in brain retinoid signalling. Behl Brain Res 2003; 145:37–49

    Article  CAS  Google Scholar 

  314. Misner DL, Jacobs S, Shimizu Y, et al. Vitamin deprivation results in reversible loss of hippocampal long-term synaptic plasticity. Proc Natl Acad Sci USA 2001; 98:11714–11719

    Article  PubMed  CAS  Google Scholar 

  315. Alfos S, Boucheron C, Pallet V, et al. 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 2001; 25:1506–1514

    Article  PubMed  CAS  Google Scholar 

  316. Corcoran JP, So PL, Maden M. Disruption of the retinoid signalling pathway causes a deposition of amyloid beta in the adult rat brain. Eur J Neurosci 2004; 20:896–902

    Article  PubMed  Google Scholar 

  317. Goodman AB, Pardee AB. Evidence for defective retinoid transport and function in late onset Alzheimer’s disease. Proc Natl Acad Sci USA 2003; 100:2901–2905

    Article  PubMed  CAS  Google Scholar 

  318. Lane MA, Bailey SJ. Role of retinoid signalling in the adult brain. Prog Neurobiol 2005; 75:275–293

    Article  PubMed  CAS  Google Scholar 

  319. Mey J, McCaffery P. Retinoic acid signaling in the nervous system of adult vertebrates. Neuroscientist 2004; 10:409–421

    Article  PubMed  CAS  Google Scholar 

  320. Sharma, R.P.Schizophrenia, epigenetics and ligand-activated nuclear receptors: a framework for chromatin therapeutics. Schizophr Res 2005; 72:79–90

    Article  PubMed  Google Scholar 

  321. Boehm MF, Zhang L, Badea BA, et al. Synthesis and structure-activity relationships of novel retinoid X receptor-selective retinoids. J Med Chem 1994; 37:2930–2941

    Article  PubMed  CAS  Google Scholar 

  322. Bischoff ED, Heyman RA, Lamph WW. Effect of the retinoid X receptor-selective ligand LGD1069 on mammary carcinoma after tamoxifen failure. J Natl Cancer Inst 1999; 91(24):2118

    Article  PubMed  CAS  Google Scholar 

  323. Hurst RE. Bexarotene ligand pharmaceuticals. Curr Opin Investig Drugs 2000; 1:514–523

    PubMed  CAS  Google Scholar 

  324. Prince HM, McCormack C, Ryan G, et al. Bexarotene capsules and gel for previously treated patients with cutaneous T-cell lymphoma: results of the Australian patients treated on phase II trials. Australas J Dermatol 2001; 42:91–97

    Article  PubMed  CAS  Google Scholar 

  325. Rigas JR, Maurer LH, Meyer LP, Hammond SM, Crisp MR, Parker BA, Truglia JA. Targretin, a selective retinoid X receptor ligand (LGD1069), vinorelbine and cisplatin for the treatment of non small cell lung cancer (NSCLC): a phase I/II trial. Paper presented at: Proc Annu Meet Am Soc Clin Oncol, 1997

    Google Scholar 

  326. Lerner V, Miodownik C, Gibel A, Kovalyonok E, Shleifer T, Goodman AB, Ritsner MS. Bexarotene as add-on to antipsychotic treatment in schizophrenia patients: a pilot open-label trial. Clin Neuropharmacol 2008; 31:25–33

    Article  PubMed  CAS  Google Scholar 

  327. Faden AI, Bogdan Stoica B. Neuroprotection. Challenges and Opportunities. Arch Neurol 2007; 64:794–800

    Article  PubMed  Google Scholar 

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Acknowledgments

The author would like to express gratitude to my colleagues Drs. Anatoly Gibel, Yael Ratner, Professor Vladimir Lerner, and Professor Abraham Weizman for fruitful cooperation. Mrs. Rena Kurs provided outstanding editorial assistance. The author gratefully acknowledges the support of the team of clinical departments of Shaar Menashe Mental Health Center. Clinical trials with neuroprotective compounds were supported by generous grants from the Stanley Foundation.

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  1. Technion – Israel Institute of Technology, Haifa, Israel

    Michael S. Ritsner

  2. Acute Department, Sha’ar Menashe Mental Health Center, Hadera, Israel

    Michael S. Ritsner

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    Michael S. Ritsner

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Ritsner, M.S. (2010). Is a Neuroprotective Therapy Suitable for Schizophrenia Patients?. In: Ritsner, M. (eds) Brain Protection in Schizophrenia, Mood and Cognitive Disorders. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-8553-5_12

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