, Volume 2, Issue 4, pp 671–682 | Cite as

Translational research in central nervous system drug discovery

  • Orest Hurko
  • John L. Ryan


Of all the therapeutic areas, diseases of the CNS provide the biggest challenges to translational research in this era of increased productivity and novel targets. Risk reduction by translational research incorporates the “learn” phase of the “learn and confirm” paradigm proposed over a decade ago. Like traditional drug discovery in vitro and in laboratory animals, it precedes the traditional phase 1–3 studies of drug development. The focus is on ameliorating the current failure rate in phase 2 and the delays resulting from suboptimal choices in four key areas: initial test subjects, dosing, sensitive and early detection of therapeutic effect, and recognition of differences between animal models and human disease. Implementation of new technologies is the key to success in this emerging endeavor.

Key Words

CNS drug discovery translational research biomarkers proteomics imaging 


  1. 1.
    Drews J. In quest of tomorrow’s medicines. New York: Springer, 1998.Google Scholar
  2. 2.
    Sheiner L. Learning versus confirming in clinical drug development. Clin Pharm Ther 61: 275–291, 1997.CrossRefGoogle Scholar
  3. 3.
    Schadt EE, Monks SA, Friend SH. A new paradigm for drug discovery: integrating clinical genetic, genomic and molecular phenotype data to identify drug targets. Biochem Soc Trans 31: 437–443, 2003.PubMedCrossRefGoogle Scholar
  4. 4.
    Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G, Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G. Correlative memory deficits, A-β elevation, and amyloid plaques in transgenic mice. Science 274: 99–103, 1996.PubMedCrossRefGoogle Scholar
  5. 5.
    Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Yao H, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St. George Hyslop P, Selkoe DJ. Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nat Med 3: 67–72, 1997.PubMedCrossRefGoogle Scholar
  6. 6.
    Saunders AM, Strittmatter WJ, Schmechel D, St. George-Hyslop PH, Pericak-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-MacLachlan DR, Alberts M, Hulette C, Crain B, Goldgaber D, Roses AD. Association of apolipoprotein E allele E4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43: 1467–1472, 1993.PubMedGoogle Scholar
  7. 7.
    Harris FM, Brecht WJ, Xu Q, Tesseur I, Kekonius L, Wyss-Coray T, Fish JD, Masliah E, Hopkins PC, Scearce-Levie K, Weisgraber KH, Mucke L, Mahley RW, Huang Y. Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer’s disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc Nat Acad Sci USA 100: 10966–10971, 2003.PubMedCrossRefGoogle Scholar
  8. 8.
    Evans RM, Hui S, Perkins A, Lahiri DK, Poirier J, Fallow MR. Cholesterol and APOE genotype interact to influence Alzheimer disease progression. Neurology 62: 1869–1871, 2004.PubMedGoogle Scholar
  9. 9.
    Dufouil C, Richard F, Fievet N, Dartigues JF, Ritchie K, Tzourio C, Amouyel P, Alperovitch A. APOE genotype, cholesterol level, lipid-lowering treatment, and dementia: the Three-City Study. Neurology 64: 1531–1538, 2005.PubMedCrossRefGoogle Scholar
  10. 10.
    Hurko O. Genetics and genomics in neuropsychopharmacology: the impact on drug discovery and development. Eur Neuropsychopharmacol 11: 491–499, 2001.PubMedCrossRefGoogle Scholar
  11. 11.
    Hurko O. The explosion of neurogenetics. Curr Opin Neurol 10: 77–83, 1997.PubMedCrossRefGoogle Scholar
  12. 12.
    Weeber EJ, Levenson JM, Sweatt JD. Molecular genetics of human cognition. Mol Interv 2: 376–391, 2002.PubMedCrossRefGoogle Scholar
  13. 13.
    Terwilliger JD, Weiss KM. Confounding, ascertainment bias, and the blind quest for a genetic ‘fountain of youth.’ Ann Med 35: 532–554, 2003.PubMedCrossRefGoogle Scholar
  14. 14.
    Terwilliger JD, Weiss KM. Linkage disequilibrium mapping of complex disease: fantasy or reality? Curr Opin Biotechnol 9: 578–594, 1998.PubMedCrossRefGoogle Scholar
  15. 15.
    Terwilliger JD, Goring HH. Gene mapping in the 20th and 21st centuries: statistical methods, data analysis, and experimental design. Hum Biol 72: 63–132, 2000.PubMedGoogle Scholar
  16. 16.
    Schadt EE, Monks SA, Friend SH. A new paradigm for drug discovery: integrating clinical genetic, genomic and molecular phenotype data to identify drug targets. Biochem Soc Trans 31: 437–443, 2003.PubMedCrossRefGoogle Scholar
  17. 17.
    Lesko LJ, Woodcock J. Pharmacogenomic-guided drug development: regulatory perspective. Pharmacogenom J 2: 20–24, 2002.CrossRefGoogle Scholar
  18. 18.
    Mirnics K, Middleton FA, Marquez A, Lewis DA, Levitt P. Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron 28: 53–67, 2000.PubMedCrossRefGoogle Scholar
  19. 19.
    Hoyle J, Phelan JP, Bermingham N, Fisher EMC. Localization of human and mouse N-ethylmaleimide-sensitive factor (NSF) gene: a two-domain member of the AAA family that is involved in membrane fusion. Mamm Genome 7: 850–852, 1996.PubMedCrossRefGoogle Scholar
  20. 20.
    Chen Q, He G, Wang XY, Chen QY, Liu XM, Gu ZZ, Liu J, Li KQ, Wang SJ, Zhu SM, Feng GY, He L. Positive association between synapsin II and schizophrenia. Biol Psychiatry 56: 177–181, 2004.PubMedCrossRefGoogle Scholar
  21. 21.
    Mimmack ML, Ryan M, Baba H, Navarro-Ruiz J, Iritani S, Faull RLM, McKenna PJ, Jones PB, Arai H, Starkey M, Emson PC, Bahn S. Gene expression analysis in schizophrenia: reproducible up-regulation of several members of the apolipoprotein L family located in a high-susceptibility locus for schizophrenia on chromosome 22. Proc Nat Acad Sci USA 99: 4680–4685, 2002.PubMedCrossRefGoogle Scholar
  22. 22.
    Jacquet H, Raux G, Thibaut F, Hecketsweiler B, Houy E, Demilly C, Haouzir S, Allio G, Fouldrin G, Drouin V, Bou J, Petit P, Campion D, Frebourg T. PRODH mutations and hyperprolinemia in a subset of schizophrenic patients. Hum Mol Genet 11: 2243–2249, 2002.PubMedCrossRefGoogle Scholar
  23. 23.
    Liu H, Heath SC, Sobin C, Roos JL, Galke BL, Blundell ML, Lenane M, Robertson B, Wijsman EM, Rapoport JL, Gogos JA, Karayiorgou M. Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia. Proc Nat Acad Sci USA 99: 3717–3722, 2002.PubMedCrossRefGoogle Scholar
  24. 24.
    Gerber DJ, Hall D, Miyakawa T, Demars S, Gogos JA, Karayiorgou M, Tonegawa S. Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin γ subunit. Proc Nat Acad Sci 100: 8993–8998, 2003.PubMedCrossRefGoogle Scholar
  25. 25.
    Miyakawa T, Leiter LM, Gerber DJ, Gainetdinov RR, Sotnikova TD, Zeng H, Caron MG, Tonegawa S. Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia. Proc Natl Acad Sci 100: 8987–8992, 2003.PubMedCrossRefGoogle Scholar
  26. 26.
    Pimm J, McQuillin A, Thirumalai S, Lawrence J, Quested D, Bass N, Lamb G, Moorey H, Datta SR, Kalsi G, Badacsonyi A, Kelly K, Morgan J, Punukollu B, Curtis D, Gurling H. The epsin 4 gene on chromosome 5q, which encodes the clathrin-associated protein enthoprotin, is involved in the genetic susceptibility to schizophrenia. Am J Hum Genet 76: 902–907, 2005.PubMedCrossRefGoogle Scholar
  27. 27.
    St. Clair D, Blackwood D, Muir W, Carothers A, Walker M, Spowart G, Gosden C, Evans HJ. Association within a family of a balanced autosomal translocation with major mental illness. Lancet 336: 13–16, 1990.PubMedCrossRefGoogle Scholar
  28. 28.
    Ekelund J, Hovatta I, Parker A, Paunio T, Varilo T, Martin R, Suhonen J, Ellonen P, Chan G, Sinsheimer JS, Sobel E, Juvonen H, Arajarvi R, Partonen T, Suvisaari J, Lonnqvist J, Meyer J, Peltonen L. Chromosome 1 loci in Finnish schizophrenia families. Hum Mol Genet 10: 1611–1617, 2001.PubMedCrossRefGoogle Scholar
  29. 29.
    Hennah W, Varilo T, Kestila M, Paunio T, Arajarvi R, Haukka J, Parker A, Martin R, Levitzky S, Partonen T, Meyer J, Lonnqvist J, Peltonen L, Ekelund J. Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects. Hum Mol Genet 12: 3151–3159, 2003.PubMedCrossRefGoogle Scholar
  30. 30.
    Freedman R, Coon H, Myles-Worsley M, Orr-Urtreger A, Olincy A, Davis A, Polymeropoulos M, Holik J, Hopkins J, Hoff M, Rosenthal J, Waldo MC, et al. Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Nat Acad Sci USA 94: 587–592, 1997.PubMedCrossRefGoogle Scholar
  31. 31.
    Stefansson H, Sarginson J, Kong A, Yates P, Steinthorsdottir V, Gudfinnsson E, Gunnarsdottir S, Walker N, Petursson H, Crombie C, Ingason A, Gulcher JR, Stefansson K, St. Clair D. Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. Am J Hum Genet 72: 83–87, 2003.PubMedCrossRefGoogle Scholar
  32. 32.
    Li T, Stefansson H, Gudfinnsson E, Cai G, Liu X, Murray RM, Steinthorsdottir V, Januel D, Gudnadottir VG, Petursson H, Ingason A, Gulcher JR, Stefansson K, Collier DA. Identification of a novel neuregulin 1 at-risk haplotype in Han schizophrenia Chinese patients, but no association with the Icelandic/Scottish risk haplotype. Mol Psychiatry 9: 698–704, 2004.PubMedGoogle Scholar
  33. 33.
    Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Putz B, Papiol S, Seaman S, Lucae S, Kohli MA, Nickel T, Kunzel HE, et al. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet 36: 1319–1325, 2004.PubMedCrossRefGoogle Scholar
  34. 34.
    Zhang X, Gainetdinov RR, Beaulieu J-M, Sotnikova TD, Burch LH, Williams RB, Schwartz DA, Krishnan KRR, Caron MG. Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 45: 11–16, 2005.PubMedCrossRefGoogle Scholar
  35. 35.
    Kustanovich V, Ishii J, Crawford L, Yang M, McGough JJ, McCracken JT, Smalle SL, Nelson SF. Transmission disequilibrium testing of dopamine-related candidate gene polymorphisms in ADHD: confirmation of association of ADHD with DRD4 and DRD5. Mol Psychiatry 9: 711–717, 2004.PubMedGoogle Scholar
  36. 36.
    Fleisher A, Grundman M, Jack CR Jr, Petersen RC, Taylor C, Kim HT, Schiller DH, Bagwell V, Sencakova D, Weiner MF, DeCarli C, DeKosky ST, van Dyck CH, Thal LJ. Alzheimer’s Disease Cooperative Study. Sex, apolipoprotein E epsilon 4 status, and hippocampal volume in mild cognitive impairment. Arch Neurol 62: 953–957, 2005.PubMedCrossRefGoogle Scholar
  37. 37.
    Brucke T, Djamshidian S, Bencsits G, Pirker W, Asenbaum S, Podreka I. SPECT and PET imaging of the dopaminergic system in Parkinson’s disease. J Neurol 247 [Suppl 4]: IV/2–7, 2000.Google Scholar
  38. 38.
    Kalra S, Arnold D. Neuroimaging in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 4: 243–248, 2003.PubMedCrossRefGoogle Scholar
  39. 39.
    Kennedy AM, Frackowiak RS, Newman SK, Bloomfield PM, Seaward J, Roques P, Lewington G, Cunningham VJ, Rossor MN. Deficits in cerebral glucose metabolism demonstrated by positron emission tomography in individuals at risk of familial Alzheimer’s disease. Neurosci Lett 186: 17–20, 1995.PubMedCrossRefGoogle Scholar
  40. 40.
    Reiman EM, Caselli RJ, Yun LS, Chen K, Bandy D, Minoshima S, Thibodeau SN, Osborne D. Preclinical evidence of Alzheimer’s disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med 334: 752–758, 1996.PubMedCrossRefGoogle Scholar
  41. 41.
    Moller PL, Juhl GI, Payen-Champenois C, Skoglund LA. Intravenous acetaminophen (paracetamol): comparable analgesic efficacy, but better local safety than its prodrug, propacetamol, for postoperative pain after third molar surgery. Anesth Analg 101: 90–96, 2005.PubMedCrossRefGoogle Scholar
  42. 42.
    McBumey DH, Balaban CD, Popp JR, Rosenkranz JE. Adaptation to capsaicin burn: effects of concentration and individual differences. Physiol Behav 72: 205–216, 2001.CrossRefGoogle Scholar
  43. 43.
    Balaban CD, McBumey DH, Affeltranger MA. Three distinct categories of time course of pain produced by oral capsaicin. J Pain 6: 315–322, 2005.PubMedCrossRefGoogle Scholar
  44. 44.
    Farina D, Arendt-Nielsen L, Graven-Nielsen T. Experimental muscle pain decreases voluntary EMG activity but does not affect the muscle potential evoked by transcutaneous electrical stimulation. Clin Neurophysiol 116: 1558–1565, 2005.PubMedCrossRefGoogle Scholar
  45. 45.
    Enggaard TP, Klitgaard NA, Sindrup SH. Specific effect of levetiracetam in experimental human pain models. Eur J Pain, 6 June 2005.Google Scholar
  46. 46.
    McKhann GM, Goldsborough MA, Borowicz LM Jr, Mellits ED, Brookmeyer R, Quaskey SA, Baumgartner WA, Cameron DE, Stuart RS, Gardner TJ. Predictors of stroke risk in coronary artery bypass patients. Ann Thorac Surg 63: 516–521, 1997.PubMedCrossRefGoogle Scholar
  47. 47.
    Restrepo L, Wityk RJ, Grega MA, Borowicz L Jr, Barker PB, Jacobs MA, Beauchamp NJ, Hillis AE, McKhann GM. Diffusion- and perfusion-weighted magnetic resonance imaging of the brain before and after coronary artery bypass grafting surgery. Stroke 33: 2909–2915, 2002.PubMedCrossRefGoogle Scholar
  48. 48.
    Parente AC, Garcia-Leal C, Del-Ben CM, Guimaraes FS, Graeff FG. Subjective and neurovegetative changes in healthy volunteers and panic patients performing simulated public speaking. Eur Neuropsychopharmacol, 13 June 2005.Google Scholar
  49. 49.
    de-Paris F, Sant’Anna MK, Vianna MR, Barichello T, Busnello JV, Kapczinski F, Quevedo J, Izquierdo I. Effects of gabapentin on anxiety induced by simulated public speaking. J Psychopharmacol 17: 184–188, 2003.PubMedCrossRefGoogle Scholar
  50. 50.
    Roelofse JA, Shipton EA, de la Harpe CJ, Blignaut RJ. Intranasal sufentanil/midazolam versus ketamine/midazolam for analgesia/sedation in the pediatric population prior to undergoing multiple dental extractions under general anesthesia: a prospective, double-blind, randomized comparison. Anesth Prog 51: 114–121, 2004.PubMedGoogle Scholar
  51. 51.
    Bell GW, Kelly PJ. A study of anxiety, and midazolam-induced amnesia in patients having lower third molar teeth extracted. Br J Oral Maxillofac Surg 38: 596–602, 2000.PubMedCrossRefGoogle Scholar
  52. 52.
    Kent JM, Papp LA, Martinez JM, Browne ST, Coplan JD, et al. Specificity of panic response to CO(2) inhalation in panic disorder: a comparison with major depression and premenstrual dysphoric disorder. Am J Psychiatry 158: 58–67, 2001.PubMedCrossRefGoogle Scholar
  53. 53.
    Bourin M, Baker GB, Bradwejn J. Neurobiology of panic disorder. J Psychosom Res 44: 163–180, 1998.PubMedCrossRefGoogle Scholar
  54. 54.
    Klein DF. False suffocation alarms, spontaneous panics, and related conditions. An integrative hypothesis. Arch Gen Psychiatry 50: 306–317, 1993.PubMedGoogle Scholar
  55. 55.
    Zwanzger P, Eser D, Aicher S, Schule C, Baghai TC, et al. Effects of alprazolam on cholecystokinin-tetrapeptideinduced panic and hypothalamic-pituitary-adrenal-axis activity: a placebo-controlled study. Neuropsychopharmacology 28: 979–984, 2003.PubMedGoogle Scholar
  56. 56.
    Bradwejn J, Koszycki D, Annable L, Couetoux du Tertre A, Reines S, Karkanias C. A dose-ranging study of the behavioral and cardiovascular effects of CCK-tetrapeptide in panic disorder. Biol Psychiatry 32: 903–912, 1992.PubMedCrossRefGoogle Scholar
  57. 57.
    Kellner M, Yassouridis A, Hua Y, Wendrich M, Jahn H, Wiedemann K. Intravenous C-type natriuretic peptide augments behavioral and endocrine effects of cholecystokinin tetrapeptide in healthy men. J Psychiatr Res 36: 16, 2002.CrossRefGoogle Scholar
  58. 58.
    Bradwejn J, Koszycki D. Imipramine antagonism of the panicogenic effects of cholecystokinin tetrapeptide in panic disorder patients. Am J Psychiatry 151: 261–263, 1994.PubMedGoogle Scholar
  59. 59.
    Zwanzger P, Baghai TC, Schuele C, Strohle A, Padberg F, et al. Vigabatrin decreases cholecystokinin-tetrapeptide (CCK-4) induced panic in healthy volunteers. Neuropsychopharmacology 25: 699–703, 2001.PubMedCrossRefGoogle Scholar
  60. 60.
    Wesnes K, Simpson P, Kidd A. An investigation of the range of cognitive impairments induced by scopolamine 0. 6 mg s.c. Hum Psychopharmacol 3: 27–41, 1988.CrossRefGoogle Scholar
  61. 61.
    Rabey JM, Neufeld MY, Treves TA, Sifris P, Korczyn AD. Cognitive effects of scopolamine in dementia. J Neural Transm 103: 873–881, 1996.PubMedCrossRefGoogle Scholar
  62. 62.
    Higgins GA, Enderlin M, Fimbel R, Haman M, Grottick AJ, Soriano M, Richards JG, Kemp JA, Gill R. Donepezil reverses a mnemonic deficit produced by scopolamine but not by perforant path lesion or transient cerebral ischaemia. Eur J Neurosci 15: 1827–1840, 2002.PubMedCrossRefGoogle Scholar
  63. 63.
    Ebert U, Kirch W. Scopolamine model of dementia: electroencephalogram findings and cognitive performance. Eur J Clin Invest 28: 944–999, 1998.PubMedCrossRefGoogle Scholar
  64. 64.
    Lahti AC, Holcomb HH. Schizophrenia, VIII: pharmacologic models. Am J Psychiatry 160: 2091, 2003.PubMedCrossRefGoogle Scholar
  65. 65.
    Passie T, Karst M, Wiese B, Emrich HM, Schneider U. Effects of different subanesthetic doses of (s)-ketamine on neuropsychology, psychopathology, and state of consciousness in man. Neuropsychobiology 51: 226–233, 2005.PubMedCrossRefGoogle Scholar
  66. 66.
    Northoff G, Richter A, Bermpohl F, Grimm S, Martin E, Marcar VL, Wahl C, Hell D, Boeker H. NMDA hypofunction in the posterior cingulate as a model for schizophrenia: an exploratory ketamine administration study in fMRI. Schizophr Res 72: 235–248, 2005.PubMedCrossRefGoogle Scholar
  67. 67.
    Becker A, Peters B, Schroeder H, Mann T, Huether G, Grecksch G. Ketamine-induced changes in rat behaviour: a possible animal model of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 27: 687–700, 2003.PubMedCrossRefGoogle Scholar
  68. 68.
    Pardridge WM. Blood-brain barrier drug targeting: the future of brain drug development. Mol Interv 3: 90–105, 2003.PubMedCrossRefGoogle Scholar
  69. 69.
    Bieck PR, Potter WZ. Biomarkers in psychotropic drug development: integration of data across multiple domains. Annu Rev Pharmacol Toxicol 45: 227–246, 2005.PubMedCrossRefGoogle Scholar
  70. 70.
    Ahmed S, Mozley PD, Potter WZ. Biomarkers in psychotropic drug development. Am J Geriatr Psychiatry 10: 678–586, 2002.PubMedGoogle Scholar
  71. 71. Scholar
  72. 72.
    Kapur S, Zipursky R, Jones C, Remington G, Houle S. Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry 157: 514–520, 2000.PubMedCrossRefGoogle Scholar
  73. 73.
    Nyberg S, Eriksson B, Oxenstiema G, Halldin C, Farde L. 1999 Suggested minimal effective dose of risperidone based on PET-measured D2 and 5-HT2A receptor occupancy in schizophrenic patients. Am J Psychiatry 156: 869–875, 1999.PubMedGoogle Scholar
  74. 74.
    Hargreaves R. Imaging substance P receptors (NK1) in the living human brain using positron emission tomography. J Clin Psychiatry 63 [Suppl 11]: 18–24, 2002.PubMedGoogle Scholar
  75. 75.
    Bergstrom M, Hargreaves RJ, Burns DH, Goldberg MR, Sciberras D, et al. Human positron emission tomography studies of brain neurokinin 1 receptor occupancy by aprepitant. Biol Psychiatry 55: 1007–1012, 2004.PubMedCrossRefGoogle Scholar
  76. 76.
    Frank R, Hargreaves R. Clinical biomarkers in drug discovery and development. Nat Rev Drug Discov 2: 566–580, 2003.PubMedCrossRefGoogle Scholar
  77. 77.
    Nau R, Zysk G, Thiel A, Range HW. Pharmacokinetic quantification of the exchange of drugs between blood and cerebrospinal fluid in man. Eur J Clin Pharmacol 45: 469–475, 1993.PubMedCrossRefGoogle Scholar
  78. 78.
    Zoli M, Jansson A, Sykova E, Agnati LF, Fuxe K. Volume transmission in the CNS and its relevance for neuropsychopharmacology. Trends Pharmacol Sci 20: 142–150, 1999.PubMedCrossRefGoogle Scholar
  79. 79.
    Fliegert F, Kurth B, Gohler K. The effects of tramadol on static and dynamic pupillometry in healthy subjects-the relationship between pharmacodynamics, pharmacokinetics and CYP2D6 metaboliser status. Eur J Clin Pharmacol 61: 257–266, 2005.PubMedCrossRefGoogle Scholar
  80. 80.
    Nikisch G, Mathe AA, Czemik A, Thiele J, Bohner J, Eap CB, Agren H, Baumann P. Long-term citalopram administration reduces responsiveness of HPA axis in patients with major depression: relationship with S-citalopram concentrations in plasma and cerebrospinal fluid (CSF) and clinical response. Psychopharmacology (Berl), 30 June 2005.Google Scholar
  81. 81.
    Vincent S, Bieck PR, Garland EM, Loghin C, Bymaster FP, et al. Clinical assessment of norepinephrine transporter blockade through biochemical and pharmacologic profile. Circulation 109: 320–327, 2004.CrossRefGoogle Scholar
  82. 82.
    Fraser GL, Riker RR. Bispectral index monitoring in the intensive care unit provides more signal than noise. Pharmacotherapy 25 [5 Pt 2]: 19S-27S, 2005.PubMedCrossRefGoogle Scholar
  83. 83.
    Vanluchene AL, Vereecke H, Thas O, Mortier EP, Shafer SL, Struys MM. Spectral entropy as an electroencephalographic measure of anesthetic drug effect: a comparison with bispectral index and processed midlatency auditory evoked response. Anesthesiology 101: 34–42, 2004.PubMedCrossRefGoogle Scholar
  84. 84.
    Buyse M, Molenberghs G. Criteria for the validation of surrogate endpoints in randomized experiments. Biometrics 54: 1014–1029, 1998.PubMedCrossRefGoogle Scholar
  85. 85.
    De Gruttola VG, Clax P, DeMets DL, et al. Considerations in the evaluation of surrogate endpoints in clinical trials: summary of a National Institutes of Health workshop. Control Clin Trials 22: 485–502, 2001.PubMedCrossRefGoogle Scholar
  86. 86.
    Rolan P, Atkinson A, Lesko LJ. Use of biomarkers from drug discovery through clinical practice: Report of the Ninth European Federation of Pharmaceutical Sciences Conference on optimizing drug development. Clin Pharm Ther 73: 284–291, 2003.CrossRefGoogle Scholar
  87. 87.
    Deleted in proof.Google Scholar
  88. 88.
    Temple R. Are surrogate markers adequate to assess cardiovascular disease drugs? JAMA 282: 790–795, 1999.PubMedCrossRefGoogle Scholar
  89. 89.
    Lonn E. The use of surrogate endpoints in clinical trials: focus on clinical trials in cardiovascular diseases. Pharmacoepidemiol Drug Saf 10: 497–508, 2001.PubMedCrossRefGoogle Scholar
  90. 90.
    Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? [comment]. Ann Intern Med 125: 605–613, 1996.PubMedGoogle Scholar
  91. 91.
    Keele MP, Voce GP. A study of bone density. Comparison of the effects of sodium fluoride, inorganic phosphate, and an anabolic sterois (oxymetholone) on demineralized bone. Am J Dis Child 118: 759–764, 1969.PubMedGoogle Scholar
  92. 92.
    Sormani MP, Bruzzi P, Comi G, Filippi M. MRI metrics as surrogate markers for clinical relapse rate in relapsing-remitting MS patients. Neurology 58: 417–421, 2002.PubMedGoogle Scholar
  93. 93.
    McDonald WI, Compston A, Edan G, Goodkin D, Haltung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 50: 121–127, 2001.PubMedCrossRefGoogle Scholar
  94. 94.
    Fazekas F, Barkhof F, Filippi M, Grossman RI, Li DK, McDonald WI, McFarland HF, Paty DW, Simon JH, Wolinsky JS, Miller DH. The contribution of magnetic resonance imaging to the diagnosis of multiple sclerosis. Neurology 53: 448–456, 1999.PubMedGoogle Scholar
  95. 95.
    Paty DW. The interferon-β 1b clinical trial and its implications for other trials. Ann Neurol 36 [Suppl]: S113-S114, 1994.PubMedCrossRefGoogle Scholar
  96. 96.
    Paty DW, Li DK. Interferon β-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Neurology 43: 662–667, 1993.PubMedGoogle Scholar
  97. 97.
    Kantarci K, Jack CR Jr. Neuroimaging in Alzheimer disease: an evidence-based review. Neuroimaging Clin N Am 13: 197–209, 2003.PubMedCrossRefGoogle Scholar
  98. 98.
    Jack CR Jr, Slomkowski M, Gracon S, Hoover TM, Felmlee JP, Stewart K, Xu Y, Shiung M, O’Brien PC, Cha R, Knopman D, Petersen RC. MRI as a biomarker of disease progression in a therapeutic trial of milameline for AD. Neurology 60: 253–260, 2003.PubMedGoogle Scholar
  99. 99.
    Jack CR Jr, Petersen RC, Xu Y, et al. Rates of hippocampal atrophy correlate with change in clinical status in aging and AD. Neurology 55: 484–489, 2000.PubMedGoogle Scholar
  100. 100.
    Mathis CA, Klunk WE, Price JC, DeKosky ST. Imaging technology for neurodegenerative diseases: progress toward detection of specific pathologies. Arch Neurol 62: 196–200, 2005.PubMedCrossRefGoogle Scholar
  101. 101.
    Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, Bergstrom M, Savitcheva I, Huang GF, Estrada S, Ausen B, Debnath ML, Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni G, Mathis CA, Langstrom B. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 55: 306–319, 2004.PubMedCrossRefGoogle Scholar
  102. 102.
    Nordberg A. PET imaging of amyloid in Alzheimer’s disease. Lancet Neurol 3: 519–527, 2004.PubMedCrossRefGoogle Scholar
  103. 103.
    Mathis CA, Wang Y, Klunk WE. Imaging β-amyloid plaques and neurofibrillary tangles in the aging human brain. Curr Pharm Des 10: 1469–1492, 2004.PubMedCrossRefGoogle Scholar
  104. 104.
    Agdeppa ED, Kepe V, Liu J, Small GW, Huang SC, Petric A, Satyamurthy N, Barrio JR. 2-Dialkylamino-6-acylmalononitrile substituted naphthalenes (DDNP analogs): novel diagnostic and therapeutic tools in Alzheimer’s disease. Mol Imaging Biol 5: 404–417, 2003.PubMedCrossRefGoogle Scholar
  105. 105.
    Alexander GE, Chen K, Pietrini P, Rapoport SI, Reiman EM. Longitudinal PET evaluation of cerebral metabolic decline in dementia: a potential outcome measure in Alzheimer’s disease treatment studies. Am J Psychiatry 159: 738–745, 2002.PubMedCrossRefGoogle Scholar
  106. 106.
    Silverman DH, Small GW, Chang CY, Lu CS, Kung De Aburto MA, Chen W, Czernin J, Rapoport SI, Pietrini P, Alexander GE, Schapiro MB, Jagust WJ, Hoffman JM, Welsh-Bohmer KA, Alavi A, Clark CM, Salmon E, de Leon MJ, Mielke R, Cummings JL, Kowell AP, Gambhir SS, Hoh CK, Phelps ME. Positron emission tomography in evaluation of dementia: regional brain metabolism and long-term outcome. JAMA 286: 2120–2127, 2001.PubMedCrossRefGoogle Scholar
  107. 107.
    Miller JD, de Leon MJ, Ferris SH, Kluger A, George AE, Reisberg B, Sachs HJ, Wolf AP. Abnormal temporal lobe response in Alzheimer’s disease during cognitive processing as measured by 11C-2-deoxy-D-glucose and PET. J Cereb Blood Flow Metab 7: 248–251, 1987.PubMedCrossRefGoogle Scholar
  108. 108.
    Galasko D. Biological markers and the treatment of Alzheimer’s disease. J Mol Neurosci 17: 119–125, 2001.PubMedCrossRefGoogle Scholar
  109. 109.
    Yuan X, Russell T, Wood G, Desiderio DM. Analysis of the human lumbar cerebrospinal fluid proteome. Electrophoresis 23: 1185–1196.Google Scholar
  110. 110.
    Terry DE, Desiderio DM. Between-gel reproducibility of the human cerebrospinal fluid proteome. Proteomics 3: 1962–1979, 2003.PubMedCrossRefGoogle Scholar
  111. 111.
    Galasko D, Chang L, Motter R, Clark CM, Kaye J, Knopman D, Thomas R, Kholodenko D, Schenk D, Lieberburg I, Miller B, Green R, Basherad R, Kertiles L, Boss MA, Seubert P. High cerebrospinal fluid tau and low amyloid β42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype. Arch Neurol 55: 937–945, 1998.PubMedCrossRefGoogle Scholar
  112. 112.
    Montine TJ, Montine KS, McMahan W, Markesbery WR, Quinn JF, Morrow JD. F2-isoprostanes in Alzheimer and other neurodegenerative diseases. Antioxid Redox Signal 7: 269–275, 2005.PubMedCrossRefGoogle Scholar
  113. 113.
    Zhang J, Goodlett DR, Quinn JF, Peskind E, Kaye JA, Zhou Y, Pan C, Yi E, Eng J, Wang Q, Aebersold RH, Montine TJ. Quantitative proteomics of cerebrospinal fluid from patients with Alzheimer disease. J Alzheimers Dis 7: 125–133, 2005.PubMedGoogle Scholar
  114. 114.
    Puchades M, Hansson SF, Nilsson CL, Andreasen N, Blennow K, Davidsson P. Proteomic studies of potential cerebrospinal fluid protein markers for Alzheimer’s disease. Brain Res Mol Brain Res 118: 140–146, 2003.PubMedCrossRefGoogle Scholar
  115. 115.
    Sultana R, Boyd-Kimball D, Poon HF, Cai J, Pierce WM, Klein JB, Markesbery WR, Zhou XZ, Lu KP, Butterfield DA. Oxidative modification and down-regulation of Pin1 in Alzheimer’s disease hippocampus: 1 redox proteomics analysis. Neurobiol Aging, 9 June 2005.Google Scholar
  116. 116.
    Castegna A, Thongboonkerd V, Klein JB, Lynn B, Markesbery WR, Butterfield DA. Proteomic identification of nitrated proteins in Alzheimer’s disease brain. J Neurochem 85: 1394–1401, 2003.PubMedCrossRefGoogle Scholar
  117. 117.
    Zhang J, Goodlett DR. Proteomic approach to studying Parkinson’s disease. Mol Neurobiol 29: 271–288, 2004.PubMedCrossRefGoogle Scholar
  118. 118.
    Mandel S, Weinreb O, Youdim MB. Using cDNA microarray to assess Parkinson’s disease models and the effects of neuroprotective drugs. Trends Pharmacol Sci 24: 184–191, 2003.PubMedCrossRefGoogle Scholar
  119. 119.
    Basso M, Giraudo S, Corpillo D, Bergamasco B, Lopiano L, Fasano M. Proteome analysis of human substantia nigra in Parkinson’s disease. Proteomics 4: 3943–3952, 2004.PubMedCrossRefGoogle Scholar
  120. 120.
    Jiang L, Lindpaintner K, Li HF, Gu NF, Langen H, He L, Fountoulakis M. Proteomic analysis of the cerebrospinal fluid of patients with schizophrenia. Amino Acids 25: 49–57, 2003.PubMedGoogle Scholar
  121. 121.
    Johnston-Wilson NL, Sims CD, Hofmann JP, Anderson L, Shore AD, Torrey EF, Yolken RH. Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium. Mol Psychiatry 5: 142–149, 2000.PubMedCrossRefGoogle Scholar
  122. 122.
    Marcotte ER, Srivastava LK, Quirion R. cDNA microarray and proteomic approaches in the study of brain diseases: focus on schizophrenia and Alzheimer’s disease. Pharmacol Ther 100: 63–74.Google Scholar
  123. 123.
    Prabakaran S, Swatton JE, Ryan MM, Huffaker SJ, Huang JT, Griffin JL, Wayland M, Freeman T, Dudbridge F, Lilley KS, Karp NA, Hester S, Tkachev D, Mimmack ML, Yolken RH, Webster MJ, Torrey EF, Bahn S. Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol Psychiatry 9: 684–697, 2004.PubMedCrossRefGoogle Scholar
  124. 124.
    Tawfik VL, LaCroix-Fralish ML, Nutile-McMenemy N, DeLeo JA. Transcriptional and translational regulation of glial activation by morphine in a rodent model of neuropathic pain. J Pharmacol Exp Ther 313: 1239–1247, 2005.PubMedCrossRefGoogle Scholar
  125. 125.
    Yu CG, Yezierski RP. Activation of the ERK1/2 signaling cascade by excitotoxic spinal cord injury. Brain Res Mol Brain Res, 9 June 2005.Google Scholar
  126. 126.
    Gineste C, Ho L, Pompl P, Bianchi M, Pasinetti GM. High-throughput proteomics and protein biomarker discovery in an experimental model of inflammatory hyperalgesia: effects of nimesulide. Drugs 63 [Suppl 1]: 23–29, 2003.PubMedCrossRefGoogle Scholar
  127. 127.
    Alzate O, Hussain SR, Goettl VM, Tewari AK, Madiai F, Stephens RL Jr, Hackshaw KV. Proteomic identification of brain-stem cytosolic proteins in a neuropathic pain model. Brain Res Mol Brain Res 128: 193–200, 2004.PubMedCrossRefGoogle Scholar
  128. 128.
    Sung HJ, Kim YS, Kim IS, Jang SW, Kim YR, Na DS, Han KH, Hwang BG, Park DS, Ko J. Proteomic analysis of differential protein expression in neuropathic pain and electroacupuncture treatment models. Proteomics 4: 2805–2813, 2004.PubMedCrossRefGoogle Scholar
  129. 129.
    Wang H, Sun H, Della Penna K, Benz RJ, Xu J, Gerhold DL, Holder DJ, Koblan KS. Chronic neuropathic pain is accompanied by global changes in gene expression and shares pathobiology with neurodegenerative diseases. Neuroscience 114: 529–546, 2002.PubMedCrossRefGoogle Scholar
  130. 130.
    Valder CR, Liu JJ, Song YH, Luo ZD. Coupling gene chip analyses and rat genetic variances in identifying potential target genes that may contribute to neuropathic allodynia development. J Neurochem 87: 560–573, 2003.PubMedCrossRefGoogle Scholar
  131. 131.
    Meincke U, Light GA, Geyer MA, Braff DL, Gouzoulis-Mayfrank E. Sensitization and habituation of the acoustic startle reflex in patients with schizophrenia. Psychiatry Res 126: 51–61, 2004.PubMedCrossRefGoogle Scholar
  132. 132.
    Roth WT, Cannon EH. Some features of the auditory evoked response in schizophrenics. Arch Gen Psychiatry 27: 466–471, 1972.PubMedGoogle Scholar
  133. 133.
    Crawford TJ, Haeger B, Kennard C, Reveley MA, Henderson L. Saccadic abnormalities in psychotic patients. II. The role of neuroleptic treatment. Psychol Med 25: 473–483, 1995.PubMedCrossRefGoogle Scholar
  134. 134.
    Ludewig K, Geyer MA, Etzensberger M, Vollenweider FX. Stability of the acoustic startle reflex, prepulse inhibition, and habituation in schizophrenia. Schizophr Res 55: 129–137, 2002.PubMedCrossRefGoogle Scholar
  135. 135.
    Siegel SJ, Maxwell CR, Majumdar S, Trief DF, Lerman C, Gur RE, Kanes SJ, Liang Y. Monoamine reuptake inhibition and nicotine receptor antagonism reduce amplitude and gating of auditory evoked potentials. Neuroscience 133: 729–738, 2005.PubMedCrossRefGoogle Scholar
  136. 136.
    Louchart-de la Chapelle S, Levillain D, Menard JF, Van der Elst A, Allio G, Haouzir S, Dollfus S, Campion D, Thibaut F. P50 inhibitory gating deficit is correlated with the negative symptomatology of schizophrenia. Psychiatry Res, 11 July 2005.Google Scholar

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© The American Society for Experimental NeuroTherapeutics, Inc 2005

Authors and Affiliations

  1. 1.Clinical Discovery, Translational ResearchWyethCollegeville

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