Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Drug development for CNS disorders: strategies for balancing risk and reducing attrition

Nature Reviews Drug Discovery volume 6, pages 521–532 (2007)Cite this article

Abstract

Disorders of the central nervous system (CNS) are some of the most prevalent, devastating and yet poorly treated illnesses. The development of new therapies for CNS disorders such as Alzheimer's disease has the potential to provide patients with significant improvements in quality of life, as well as reduce the future economic burden on health-care systems. However, few truly innovative CNS drugs have been approved in recent years, suggesting that there is a considerable need for strategies to enhance the productivity of research and development in this field. In this article, using illustrative examples from neurological and psychiatric disorders, we describe various approaches that are being taken to discover CNS drugs, discuss their relative merits and consider how risk can be balanced and attrition reduced.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Different approaches to CNS drug discovery.
Figure 2: Pursuing multiple targets in a favoured pathway: the amyloid cascade.
Figure 3: Differentiating symptomatic and disease-modifying therapies.

Similar content being viewed by others

References

  1. Pharmaceutical Research and Manufacturers of America (PhRMA). New Medicines in Development for Mental Illness. PhRMA web site [online], (2006).

  2. Pharmaceutical Research and Manufacturers of America (PhRMA). New Medicines in Development for Neurological Disorders. PhRMA web site [online], (2006).

  3. Ferri, C. P. et al. Global prevalence of dementia: a Delphi consensus study. Lancet 366, 2112–2117 (2005).

    PubMed  PubMed Central  Google Scholar 

  4. Kola, I. & Landis, J. Can the pharmaceutical industry reduce attrition rates? Nature Rev. Drug Discov. 3, 711–715 (2004).

    CAS  Google Scholar 

  5. Tufts Center for the Study of Drug Development. Longer clinical times are extending time to market for new drugs in US. Tufts CSDD Impact Report 7, 1–4 (2005).

  6. Bornstein, N., Silvestrelli, G., Caso, V. & Parnetti, L. Arterial hypertension and stroke prevention: an update. Clin. Exp. Hypertens. 28, 317–326 (2006).

    PubMed  Google Scholar 

  7. Sato, A., Saruta, T. & Funder J. W. Combination therapy with aldosterone blockade and renin-angiotensin inhibitors confers organ protection. Hypertens. Res. 29, 211–216 (2006).

    CAS  PubMed  Google Scholar 

  8. Nitsch, R. M., Slack, B. E., Wurtman, R. J. & Growdon, J. H. Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 258, 304–307 (1992).

    CAS  PubMed  Google Scholar 

  9. Pangalos, M. N., Jacobsen, S. J. & Reinhart, P. H. Disease modifying strategies for the treatment of Alzheimer's disease targeted at modulating levels of the β-amyloid peptide. Biochem. Soc. Trans. 33, 553–558 (2005).

    CAS  PubMed  Google Scholar 

  10. Dominguez, D. I. & De Strooper, B. Novel therapeutic strategies provide the real test for the amyloid hypothesis of Alzheimer's disease. Trends Pharmacol. Sci. 23, 324–330 (2002).

    CAS  PubMed  Google Scholar 

  11. Zhang, L. et al. Characterization of the reconstituted γ-secretase complex from Sf9 cells co-expressing presenilin 1, nicastrin, aph-1a, and pen-2. Biochemistry 44, 4450–4457 (2005).

    CAS  PubMed  Google Scholar 

  12. Marambaud, P. et al. A presenilin-1/γ-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J. 21, 1948–1956 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Roberds, S. L. et al. BACE knockout mice are healthy despite lacking the primary β-secretase activity in brain: implications for Alzheimer's disease therapeutics. Hum. Mol. Genet. 10, 1317–1324 (2001).

    CAS  PubMed  Google Scholar 

  14. Hong, L. et al. Crystal structure of memapsin 2 (β-secretase) in complex with an inhibitor OM00–3. Biochemistry 41, 10963–10967 (2002).

    CAS  PubMed  Google Scholar 

  15. Booth, B. & Zemmel, R. Prospects for productivity. Nature Rev. Drug Discov. 3, 451–456 (2004).

    CAS  Google Scholar 

  16. Hornig, C. R. et al. CT contrast enhancement on brain scans and blood–CSF barrier disturbances in cerebral ischemic infarction. Stroke 16, 268–273 (1985).

    CAS  PubMed  Google Scholar 

  17. Papadopoulos, C. M. et al. Dendritic plasticity in the adult rat following middle cerebral artery occlusion and Nogo-a neutralization. Cereb. Cortex 16, 529–536 (2006).

    PubMed  Google Scholar 

  18. Schenk, D. et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173–177 (1999).

    CAS  PubMed  Google Scholar 

  19. Bard, F. et al. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nature Med. 6, 916–919 (2000).

    CAS  PubMed  Google Scholar 

  20. Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. (Berl.) 82, 239–259 (1991).

    CAS  Google Scholar 

  21. Akiyama, H. et al. Inflammation and Alzheimer's disease. Neurobiol. Aging 21, 383–421 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Reddy, P. & Beal, M. Are mitochondria critical in the pathogenesis of Alzheimer's disease? Brain Res. Brain Res. Rev. 49, 618–632 (2005).

    CAS  PubMed  Google Scholar 

  23. Kivipelto, M. et al. Apolipoprotein E ɛ4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann. Intern. Med. 137, 149–155 (2002).

    CAS  PubMed  Google Scholar 

  24. Brunton, V. G. et al. Identification of Src-specific phosphorylation site on focal adhesion kinase: dissection of the role of Src SH2 and catalytic functions and their consequences for tumor cell behavior. Cancer Res. 65, 1335–1342 (2005).

    CAS  PubMed  Google Scholar 

  25. Paul, R. et al. Src deficiency or blockade of Src activity in mice provides cerebral protection following stroke. Nature Med. 7, 222–227 (2001).

    CAS  PubMed  Google Scholar 

  26. Lebovitz, H. Diabetes: assessing the pipeline. Atheroscler. Suppl. 7, 43–49 (2006).

    PubMed  Google Scholar 

  27. Feinstein, D. L. et al. Peroxisome proliferator-activated receptor-γ agonists prevent experimental autoimmune encephalomyelitis. Ann. Neurol. 51, 694–702 (2002).

    CAS  PubMed  Google Scholar 

  28. Heneka, M. T., Landreth, G. E. & Feinstein, D. L. Role for peroxisome proliferator-activated receptor-γ in Alzheimer's disease. Ann. Neurol. 49, 276 (2001).

    CAS  PubMed  Google Scholar 

  29. Rosenzweig-Lipson, S. et al. Antiobesity-like effects of the 5-HT2C receptor agonist WAY-161503. Brain Res. 1073–1074, 240–251 (2006).

    PubMed  Google Scholar 

  30. Schechter, L. et al. Innovative approaches for the development of antidepressant drugs: current and future strategies. NeuroRx 2, 590–611 (2005).

    PubMed  PubMed Central  Google Scholar 

  31. Porter R. H. et al. A clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive mGlu5 receptor antagonist with inverse agonist activity. J. Pharmacol. Exp. Ther. 315, 711–721 (2005).

    CAS  PubMed  Google Scholar 

  32. Miyamoto, S., Duncan, G. E., Marx, C. E. & Lieberman, J. A. Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol. Psychiatry 10, 79–104 (2005).

    CAS  PubMed  Google Scholar 

  33. Braff, D. L. L., G. A. . The use of neurophysiological endophenotypes to understand the genetic basis of schizophrenia. Dialogues Clin. Neurosci. 7, 125–135 (2005).

    PubMed  PubMed Central  Google Scholar 

  34. Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 30, 2752–2758 (1999).

  35. Lees, K. R. et al. NXY-059 for acute ischemic stroke. N. Engl. J. Med. 354, 588–600 (2006).

    CAS  PubMed  Google Scholar 

  36. Ireland, R. Is NXY-059 beneficial in ischemic stroke? Nature Clin. Pract. Cardiovasc. Med. 3, 240–241 (2006).

    Google Scholar 

  37. Fong, J. J. & Rhoney, D. H. NXY-059: review of neuroprotective potential for acute stroke. Ann. Pharmacother. 40, 461–471 (2006).

    CAS  PubMed  Google Scholar 

  38. [No Authors Listed]. The Bitterest pill. Nature 444, 532–533 (2006).

  39. Leow, A. D. et al. Longitudinal stability of MRI for mapping brain change using tensor-based morphometry. Neuroimage 31, 627–640 (2006).

    PubMed  Google Scholar 

  40. Schenk, D., Games, K. D. & McConlogue, L. The potential utility of transgenic mice harboring β-amyloid precursor protein. Neurobiol. Aging 16, 711–713 (1995).

    CAS  PubMed  Google Scholar 

  41. Bloom, F. E. et al. Mouse models of human neurodegenerative disorders: requirements for medication development. Arch. Neurol. 62, 185–187 (2005).

    PubMed  Google Scholar 

  42. Harrison, S. M. et al. BACE1 (β-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes. Mol. Cell. Neurosci. 24, 646–55 (2003).

    CAS  PubMed  Google Scholar 

  43. Laird, F. M. et al. BACE1, a major determinant of selective vulnerability of the brain to amyloid-β amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J. Neurosci. 25, 11693–11709 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Roher, A. E. & Kokjohn, T. A. Appraisal of AβPP transgenic mice as models for Alzheimer's disease amyloid cascade. Curr. Med. Chem. 3, 85–90 (2003).

    CAS  Google Scholar 

  45. Lehmann, H. E. & Ban, T. A. The history of the psychopharmacology of schizophrenia. Can. J. Psychiatry 42, 152–162 (1997).

    CAS  PubMed  Google Scholar 

  46. Janssen, P. A., Niemegeers, C. J. & Schellekens, K. H. Is it possible to predict the clinical effects of neuroleptic drugs (major tranquillizers) from animal data?I. 'Neuroleptic Activity Spectra' for rats. Arzneimittelforschung. 15, 104–117 (1965).

    CAS  PubMed  Google Scholar 

  47. Costall, B., Naylor, R. J. & Nohria, V. Climbing behaviour induced by apomorphine in mice: a potential model for the detection of neuroleptic activity. Eur. J. Pharmacol. 50, 39–50 (1978).

    CAS  PubMed  Google Scholar 

  48. Braff, D. L. & Geyer, M. A. Sensorimotor gating and schizophrenia. Human and animal model studies. Arch. Gen. Psychiatry 47, 181–188 (1990).

    CAS  PubMed  Google Scholar 

  49. Lipska, B. & Weinberger, D. To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology 23, 223–239 (2000).

    CAS  PubMed  Google Scholar 

  50. Cryan, J., Markou, A. & Lucki, I. Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol. Sci. 23, 238–245 (2002).

    CAS  PubMed  Google Scholar 

  51. Rupniak, N. M. & Kramer, M. S. Discovery of the antidepressant and anti-emetic efficacy of substance P receptor (NK1) antagonists. Trends Pharmacol. Sci. 20, 485–490 (1999).

    CAS  PubMed  Google Scholar 

  52. Herpfer, I. & Lieb, K. Substance P receptor antagonists in psychiatry: rationale for development and therapeutic potential. CNS Drugs 19, 275–293 (2005).

    CAS  PubMed  Google Scholar 

  53. Ranga, K. & Krishnan, R. Clinical experience with substance P receptor (NK1) antagonists in depression. J. Clin. Psychiatry. 63 (Suppl. 11), 25–29 (2002).

    CAS  PubMed  Google Scholar 

  54. Frank, R. & Hargreaves, R. Clinical biomarkers in drug discovery and development. Nature Rev. Drug Discov. 2, 566–280 (2003).

    CAS  Google Scholar 

  55. Nestler, E. et al. Preclinical models: Status of basic research in depression. Biol. Psychiatry 52, 503–528 (2002).

    PubMed  Google Scholar 

  56. Risch, N. & Botstein, D. A manic depressive history. Nature Genet. 12, 351–353 (1996).

    CAS  PubMed  Google Scholar 

  57. Terwilliger, J. On the resolution and feasibility of genome scanning approaches. Adv. Genet. 42, 351–391 (2001).

    CAS  PubMed  Google Scholar 

  58. Harrison, P. & Weinberger, D. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol. Psychiatry 10, 40–68 (2005).

    CAS  PubMed  Google Scholar 

  59. Kamiya, A. et al. A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex: development. Nature Cell Biol. 7, 1167–1178 (2005).

    PubMed  Google Scholar 

  60. Rawlins, M. D. Cutting the cost of drug development? Nature Rev. Drug Discov. 3, 360–364 (2004).

    CAS  Google Scholar 

  61. Sheiner, L. Learning versus confirming in clinical drug development. Clin. Pharm. Ther. 61, 275–291 (1997).

    CAS  Google Scholar 

  62. Whalley, L., Deary, I., Appleton, C. & Starr, J. Cognitive reserve and the neurobiology of cognitive aging. Ageing Res. Rev. 3, 369–382 (2004).

    PubMed  Google Scholar 

  63. Winblad, B. & Poritis, N. Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine). Int. J. Geriatr. Psychiatry 14, 135–146 (1999).

    CAS  PubMed  Google Scholar 

  64. Rush, A. J. et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N. Engl. J. Med. 354, 1231–1242 (2006).

    CAS  PubMed  Google Scholar 

  65. Trivedi, M. H. et al. Medication augmentation after the failure of SSRIs for depression. N. Engl. J. Med. 354, 1243–1252 (2006).

    CAS  PubMed  Google Scholar 

  66. Wolf, C. R. & Smith, G. Cytochrome P450 CYP2D6. IARC Sci. Publ. 148, 209–229 (1999).

    CAS  Google Scholar 

  67. Emilien, G., Ponchon, M., Caldas, C., Isacson, O. & Maloteaux, J. M. Impact of genomics on drug discovery and clinical medicine. Q. J. Med. 93, 391–423 (2000).

    CAS  Google Scholar 

  68. Poulsen, L. et al. Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects. Eur. J. Clin. Pharmacol. 51, 289–295 (1996).

    CAS  PubMed  Google Scholar 

  69. Defilippi, J. L. & Crismon, M. L. Drug interactions with cholinesterase inhibitors. Drugs Aging 20, 437–444 (2003).

    CAS  PubMed  Google Scholar 

  70. Smeraldi, E. et al. Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol. Psychiatry 3, 508–511 (1998).

    CAS  PubMed  Google Scholar 

  71. Lane, H. Y. et al. Association of risperidone treatment response with a polymorphism in the 5-HT(2A) receptor gene. Am. J. Psychiatry 159, 1593–1595 (2002).

    PubMed  Google Scholar 

  72. Roses, A. D. et al. Complex disease-associated pharmacogenetics: drug efficacy, drug safety, and confirmation of a pathogenetic hypothesis (Alzheimer's disease). Pharmacogenomics J. 7, 10–28 (2007).

    CAS  PubMed  Google Scholar 

  73. Tsuang, M. T. & Faraone, S. V. Genetics of Alzheimer's disease. J. Formos. Med. Assoc. 95, 733–740 (1996).

    CAS  PubMed  Google Scholar 

  74. Klimas, M. Positron emission tomography and drug discovery: contributions to the understanding of pharmacokinetics, mechanism of action and disease state characterization. Mol. Imaging Biol. 4, 311–337 (2002).

    PubMed  Google Scholar 

  75. Dawson, D. A., Wadsworth, G. & Palmer, A. M. A comparative assessment of the efficacy and side-effect liability of neuroprotective compounds in experimental stroke. Brain Res. 892, 344–350 (2001).

    CAS  PubMed  Google Scholar 

  76. Matsuoka, Y. et al. An Aβ sequestration approach using non-antibody Aβ binding agents. Curr. Alzheimer Res. 2, 265–268 (2005).

    CAS  PubMed  Google Scholar 

  77. Kayed, R. et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300, 486–489 (2003).

    CAS  PubMed  Google Scholar 

  78. Motter, R. et al. Reduction of β-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer's disease. Ann. Neurol. 38, 643–648 (1995).

    CAS  PubMed  Google Scholar 

  79. Lewczuk, P. et al. Tau protein phosphorylated at threonine 181 in CSF as a neurochemical biomarker in Alzheimer's disease: Original data and review of the literature. J. Mol. Neurosci. 23, 115–122 (2004).

    CAS  PubMed  Google Scholar 

  80. Pratico, D. & Sung, S. Lipid peroxidation and oxidative imbalance: early functional events in Alzheimer's disease. J. Alzheimers Dis. 6, 171–175 (2004).

    CAS  PubMed  Google Scholar 

  81. Renna, M., Handy, J. & Shah, A. Low baseline Bispectral Index of the electroencephalogram in patients with dementia. Anesth. Analg. 96, 1380–1385 (2003).

    PubMed  Google Scholar 

  82. LeBlanc, J., Dasta, J. & Kane-Gill, S. Role of the bispectral index in sedation monitoring in the ICU. Ann. Pharmacother. 40, 490–500 (2006).

    PubMed  Google Scholar 

  83. Herrmann, C. & Demiralp, T. Human EEG γ oscillations in neuropsychiatric disorders. Clin. Neurophysiol. 116, 2719–2733 (2005).

    CAS  PubMed  Google Scholar 

  84. Mohs, R. et al. Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer's Disease Assessment Scale that broaden its scope. The Alzheimer's Disease Cooperative Study. Alzheimer Dis. Assoc. Disord. 11 (Suppl. 2), 13–21 (1997).

    Google Scholar 

  85. Solomon, P. et al. Classical conditioning in patients with Alzheimer's disease: a multiday study. Psychol. Aging 10, 248–254 (1995).

    CAS  PubMed  Google Scholar 

  86. Skelton, R., Ross, S., Nerad, L. & Livingstone, S. Human spatial navigation deficits after traumatic brain injury shown in the arena maze, a virtual Morris water maze. Brain Inj. 20, 189–203 (2006).

    PubMed  Google Scholar 

  87. Pariente, J. et al. Alzheimer's patients engage an alternative network during a memory task. Ann Neurol 58, 870–879 (2005).

    PubMed  Google Scholar 

  88. Frank, R. A. et al. Biological markers for therapeutic trials in Alzheimer's disease. Proceedings of the biological markers working group; NIA initiative on neuroimaging in Alzheimer's disease. Neurobiol. Aging 24, 521–536 (2003).

    PubMed  Google Scholar 

  89. Klunk, W. et al. Binding of the positron emission tomography tracer Pittsburgh compound-B reflects the amount of amyloid-β in Alzheimer's disease brain but not in transgenic mouse brain. J. Neurosci. 25, 10598–10606 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Kung, M., Zhuang, Z., Hou, C. & Kung, H. Development and evaluation of iodinated tracers targeting amyloid plaques for SPECT imaging. J. Mol. Neurosci. 24, 49–53 (2004).

    CAS  PubMed  Google Scholar 

  91. Versijpt, J. et al. Assessment of neuroinflammation and microglial activation in Alzheimer's disease with radiolabelled PK11195 and single photon emission computed tomography. A pilot study. Eur. Neurol. 50, 39–47 (2003).

    CAS  PubMed  Google Scholar 

  92. Johnson, N. et al. Pattern of cerebral hypoperfusion in Alzheimer disease and mild cognitive impairment measured with arterial spin-labeling MR imaging: initial experience. Radiology 234, 851–859 (2005).

    PubMed  Google Scholar 

  93. Han, S., Nestor, P. & Wible, C. fMRI of lexical-semantic priming in a chronic schizophrenia patient. Appl. Neuropsychol. 13, 51–57 (2006).

    PubMed  Google Scholar 

  94. Chudasama, Y. & Robbins, T. W. Dopaminergic modulation of visual attention and working memory in the rodent prefrontal cortex. Neuropsychopharmacology 29, 1628–1636 (2004).

    CAS  PubMed  Google Scholar 

  95. Spinelli, S. et al. Performance of the marmoset monkey on computerized tasks of attention and working memory. Brain Res. Cogn. Brain Res. 19, 123–137 (2004).

    PubMed  Google Scholar 

  96. Spinelli, S. et al. Effects of the mGluR2/3 agonist LY354740 on computerized tasks of attention and working memory in marmoset monkeys. Psychopharmacology (Berl.) 179, 292–302 (2005).

    CAS  Google Scholar 

  97. Olson, H. et al. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul. Toxicol. Pharmacol. 32, 56–67 (2000).

    CAS  PubMed  Google Scholar 

  98. Huby, R. & Tugwood, J. D. Gene expression profiling for pharmaceutical safety assessment. Expert Opin. Drug Metab. Toxicol. 1, 247–260 (2005).

    CAS  PubMed  Google Scholar 

  99. Drazen, J. M. Patients at risk. N. Engl. J. Med. 353, 417 (2005).

    CAS  PubMed  Google Scholar 

  100. O'Toole, M. et al. Risk factors associated with β-amyloid(1–42) immunotherapy in preimmunization gene expression patterns of blood cells. Arch. Neurol. 62, 1531–1536 (2005).

    PubMed  Google Scholar 

  101. Davies, P. & Maloney, A. J. Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet 2, 1403 (1976).

    CAS  PubMed  Google Scholar 

  102. Bowen, D. M., Smith, C. B., White, P. & Davison, A. N. Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain 99, 459–496 (1976).

    CAS  PubMed  Google Scholar 

  103. Perry, E. K., Perry, R. H., Blessed, G. & Tomlinson, B. E. Necropsy evidence of central cholinergic deficits in senile dementia. Lancet 1, 189 (1977).

    CAS  PubMed  Google Scholar 

  104. Whitehouse, P. J. et al. Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science 215, 1237–1239 (1982).

    CAS  PubMed  Google Scholar 

  105. Bartus, R. T., Dean, R. L. 3rd, Beer, B. & Lippa, A. S. The cholinergic hypothesis of geriatric memory dysfunction. Science 217, 408–414 (1982).

    CAS  PubMed  Google Scholar 

  106. Ferrante, R. J., Kowall, N. W. & Richardson, E. P. Jr . Proliferative and degenerative changes in striatal spiny neurons in Huntington's disease: a combined study using the section-Golgi method and calbindin D28k immunocytochemistry. J. Neurosci. 11, 3877–3887 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Francis, P. T. et al. Antemortem measurements of neurotransmission: possible implications for pharmacotherapy of Alzheimer's disease and depression. J. Neurol. Neurosurg. Psychiatry 56, 80–84 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Schechter, L. et al. Lecozotan (SRA-333): A selective serotonin 1A receptor antagonist that enhances the stimulated release of glutamate and acetylcholine in the hippocampus and possesses cognitive-enhancing properties. J. Pharmacol. Exp. Ther. 314, 1274–1289 (2005).

    CAS  PubMed  Google Scholar 

  109. King, M. V. et al. 5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation — an effect sensitive to NMDA receptor antagonism. Neuropharmacology 47, 195–204 (2004).

    CAS  PubMed  Google Scholar 

  110. Komater, V. A. et al. H3 receptor blockade by thioperamide enhances cognition in rats without inducing locomotor sensitization. Psychopharmacology (Berl.) 167, 363–372 (2003).

    CAS  Google Scholar 

  111. Selkoe, D. J. & Schenk, D. Alzheimer's disease: molecular understanding predicts amyloid-based therapeutics. Annu. Rev. Pharmacol. Toxicol. 43, 545–584 (2003).

    CAS  PubMed  Google Scholar 

  112. St George-Hyslop, P. H. & Petit, A. Molecular biology and genetics of Alzheimer's disease. C. R. Biol. 328, 119–130 (2005).

    CAS  PubMed  Google Scholar 

  113. Podlisny, M. B., Lee, G. & Selkoe, D. J. Gene dosage of the amyloid β precursor protein in Alzheimer's disease. Science 238, 669–671 (1987).

    CAS  PubMed  Google Scholar 

  114. DeMattos, R. B. et al. ApoE and clusterin cooperatively suppress Aβ levels and deposition. Evidence that ApoE regulates extracellular Aβ metabolism in vivo. Neuron 41, 193–202 (2004).

    CAS  PubMed  Google Scholar 

  115. Klein, W. L. Aβ toxicity in Alzheimer's disease: globular oligomers (ADDLs) as new vaccine and drug targets. Neurochem. Int. 41, 345–352 (2002).

    CAS  PubMed  Google Scholar 

  116. Lesne, S. et al. A specific amyloid-β protein assembly in the brain impairs memory. Nature 440, 352–357 (2006).

    CAS  PubMed  Google Scholar 

  117. Walsh, D. M. et al. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535–539 (2002).

    CAS  PubMed  Google Scholar 

  118. Jacobsen, J. S., Reinhart, P. & Pangalos, M. N. Current concepts in therapeutic strategies targeting cognitive decline and disease modification in Alzheimer's disease. NeuroRx 2, 612–626 (2005).

    PubMed  PubMed Central  Google Scholar 

  119. Carlsson, A., Jonason, J., Lindqvist, M. & Fuxe, K. Demonstration of extraneuronal 5-hydroxytryptamine accumulation in brain following membrane-pump blockade by chlorimipramine. Brain Res. 2, 456–460 (1969).

    Google Scholar 

  120. Goodwin, F. & Bunney, W. J. Depressions following reserpine: A reevaluation. Semin. Psychiatry 3, 435–448 (1971).

    CAS  PubMed  Google Scholar 

  121. Hirschfeld, R. History and evolution of the monoamine hypothesis of depression. J. Clin. Psychiatry 61, 4–6 (2000).

    CAS  PubMed  Google Scholar 

  122. Artigas, F., Romero, L., de Montigny, C. & Blier, P. Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists. Trends Neurosci. 19, 378–383 (1996).

    CAS  PubMed  Google Scholar 

  123. Merikangas, K. & Risch, N. Will the genomics revolution revolutionize psychiatry? Am. J. Psychiatry 160, 625–635 (2003).

    PubMed  Google Scholar 

  124. Hasler, G., Drevets, W., Manji, H. & Charney, D. Discovering endophenotypes for major depression. Neuropsychopharmacology 29, 1765–1781 (2004).

    CAS  PubMed  Google Scholar 

  125. Kinney, D. et al. Season of birth and obstetrical complications in schizophrenics. J. Psychiatr. Res. 28, 499–509 (1994).

    CAS  PubMed  Google Scholar 

  126. Kelly, B., Lane, A., Agartz, I., Henriksson, K. & McNeil, T. Craniofacial dysmorphology in Swedish schizophrenia patients. Acta Psychiatr. Scand. 111, 202–207 (2005).

    CAS  PubMed  Google Scholar 

  127. Sheline, Y., Gado, M. & Kraemer, H. Untreated depression and hippocampal volume loss. Am. J Psychiatry 160, 1516–1518 (2003).

    PubMed  Google Scholar 

  128. Sheline, Y., Wang, P., Gado, M., Csernansky, J. & Vannier, M. Hippocampal atrophy in recurrent major depression. Proc. Natl Acad. Sci. USA 93, 3908–3913 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Malberg, J., Eisch, A., Nestler, E. & Duman, R. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J. Neurosci. 20, 9104–9110 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank K. Charles, G. Burr and M. Glick for thoughtful comments and review of the manuscript. N. Bryan for providing help with the images in figure 2. We would also like to thank M. Weiner, University of California, San Francisco, as well as B. Miller, N. Schuff and D. Antao for providing the images in figure 3.

Author information

Authors and Affiliations

  1. Menelas N. Pangalos and Lee E. Schechter are at Wyeth Research, Neuroscience Discovery, CN800, Princeton, New Jersey 08543, USA.,

    Menelas N. Pangalos & Lee E. Schechter

  2. Orest Hurko is at Wyeth Research, Translational Research, Collegeville, Pennsylvania 19426, USA.,

    Orest Hurko

Authors
  1. Menelas N. Pangalos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lee E. Schechter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Orest Hurko
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Menelas N. Pangalos.

Ethics declarations

Competing interests

All authors are employees of Wyeth Pharmaceuticals and own shares and company stock options.

Related links

Related links

DATABASES

OMIM

Alzheimer's disease

Migraine

Multiple sclerosis

Parkinson's disease

Schizophrenia

FURTHER INFORMATION

Alzheimer's Disease Neuroimaging Initiative

CANTAB

Treatment Units for Research on Neurocognition and Schizophrenia

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pangalos, M., Schechter, L. & Hurko, O. Drug development for CNS disorders: strategies for balancing risk and reducing attrition. Nat Rev Drug Discov 6, 521–532 (2007). https://doi.org/10.1038/nrd2094

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2094

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing