Disease progression and neuroscience

Review Paper

Abstract

The concepts of disease progression are discussed in the context of neurological disorders. The importance of understanding the time course of the response to inactive (placebo) treatment is discussed. Disease progression and response to placebo treatment both need to be considered before drug effects can be reliably identified. Criteria for distinguishing between symptomatic and disease modifying drug effects are proposed and used to interpret the results of clinical trials in pain, depression, schizophrenia, stroke, Alzheimer’s disease and Parkinson’s disease.

Keywords

Disease progression Neuroprotection Disease modifying Neuroscience Alzheimer’s Parkinson’s 

References

  1. 1.
    Kennedy WP (1961) The nocebo reaction. Med World 95:203–205PubMedGoogle Scholar
  2. 2.
    Wells RE, Kaptchuk TJ (2012) To tell the truth, the whole truth, may do patients harm: the problem of the nocebo effect for informed consent. Am J Bioeth 12(3):22–29. doi:10.1080/15265161.2011.652798 PubMedCrossRefGoogle Scholar
  3. 3.
    Hauser W, Bartram C, Bartram-Wunn E, Tolle T (2012) Adverse events attributable to nocebo in randomized controlled drug trials in fibromyalgia syndrome and painful diabetic peripheral neuropathy: systematic review. Clin J Pain 28(5):437–451. doi:10.1097/AJP.0b013e3182321ad8 PubMedCrossRefGoogle Scholar
  4. 4.
    Holford NH, Peace KE (1992) Methodologic aspects of a population pharmacodynamic model for cognitive effects in Alzheimer patients treated with tacrine. Proc Natl Acad Sci USA 89(23):11466–11470PubMedCrossRefGoogle Scholar
  5. 5.
    Mandema JW, Stanski DR (1996) Population pharmacodynamic model for ketorolac analgesia. Clin Pharmacol Ther 60(6):619–635PubMedCrossRefGoogle Scholar
  6. 6.
    Wang X, Shang D, Ribbing J, Ren Y, Deng C, Zhou T, Guo F, Lu W (2012) Placebo effect model in asthma clinical studies: longitudinal meta-analysis of forced expiratory volume in 1 second. Eur J Clin Pharmacol 68(8):1157–1166. doi:10.1007/s00228-012-1245-2 PubMedCrossRefGoogle Scholar
  7. 7.
    Vu TC, Nutt JG, Holford NHG (2012) Progression of motor and nonmotor features of Parkinson’s disease and their response to treatment. Br J Clin Pharmacol 74(2):267–283. doi:10.1111/j.1365-2125.2012.04192.x PubMedCrossRefGoogle Scholar
  8. 8.
    Holford NH, Nutt JG (2011) Interpreting the results of Parkinson’s disease clinical trials: time for a change. Mov Disord 26(4):569–577. doi:10.1002/mds.23555 PubMedCrossRefGoogle Scholar
  9. 9.
    Henchcliffe C, Severt WL (2011) Disease modification in Parkinson’s disease. Drugs Aging 28(8):605–615. doi:10.2165/11591320-000000000-00000 PubMedCrossRefGoogle Scholar
  10. 10.
    Seidl SE, Potashkin JA (2011) The promise of neuroprotective agents in Parkinson’s disease. Frontiers Neurol 2:1–19. doi:10.3389/fneur.2011.00068 Google Scholar
  11. 11.
    Sheiner LB (1994) A new approach to the analysis of analgesic drug trials, illustrated with bromfenac data. Clin Pharmacol Ther 56(3):309–322PubMedCrossRefGoogle Scholar
  12. 12.
    Anderson BJ, Woollard GA, Holford NH (2001) Acetaminophen analgesia in children: placebo effect and pain resolution after tonsillectomy. Eur J Clin Pharmacol 57(8):559–569PubMedCrossRefGoogle Scholar
  13. 13.
    Russu A, Marostica E, De Nicolao G, Hooker AC, Poggesi I, Gomeni R, Zamuner S (2012) Joint modeling of efficacy, dropout, and tolerability in flexible-dose trials: a case study in depression. Clin Pharmacol Ther 91(5):863–871. doi:10.1038/clpt.2011.322 PubMedCrossRefGoogle Scholar
  14. 14.
    Gomeni R, Merlo-Pich E (2007) Bayesian modelling and ROC analysis to predict placebo responders using clinical score measured in the initial weeks of treatment in depression trials. Br J Clin Pharmacol 63(5):595–613. doi:10.1111/j.1365-2125.2006.02815.x PubMedCrossRefGoogle Scholar
  15. 15.
    Reeves RR, Ladner ME, Hart RH, Burke RS (2007) Nocebo effects with antidepressant clinical drug trial placebos. Gen Hosp Psychiatry 29(3):275–277. doi:10.1016/j.genhosppsych.2007.01.010 PubMedCrossRefGoogle Scholar
  16. 16.
    Mora MS, Nestoriuc Y, Rief W (2011) Lessons learned from placebo groups in antidepressant trials. Philos Trans R Soc Lond B Biol Sci 366(1572):1879–1888. doi:10.1098/rstb.2010.0394 PubMedCrossRefGoogle Scholar
  17. 17.
    Holford NHG (2005) The time course of placebo response in clinical trials—do antidepressants really take two weeks to work?. AAPS Annual Meeting 2005, Nashville, TN http://holford.fmhs.auckland.ac.nz/docs/AAPS_Placebo_&_Anti-depressant_Response.ppt.pdf. Accessed 12 Aug 2012
  18. 18.
    Holford N (2012) Modeling helps in understanding antidepressants. Clin Pharmacol Ther 92(2):155–156. doi:10.1038/clpt.2012.88 PubMedCrossRefGoogle Scholar
  19. 19.
    Waddington JL, Scully PJ, Youssef HA (1997) Developmental trajectory and disease progression in schizophrenia: the conundrum, and insights from a 12-year prospective study in the Monaghan 101. Schizophr Res 23(2):107–118. doi:10.1016/s0920-9964(96)00111-9 PubMedCrossRefGoogle Scholar
  20. 20.
    Holmes E, Tsang TM, Huang JTJ, Leweke FM, Koethe D, Gerth CW, Nolden BM, Gross S, Schreiber D, Nicholson JK, Bahn S (2006) Metabolic Profiling of CSF: evidence that early intervention may impact on disease progression and outcome in schizophrenia. PLoS Med 3(8):e327. doi:10.1371/journal.pmed.0030327 PubMedCrossRefGoogle Scholar
  21. 21.
    Kimko HC, Reele SS, Holford NH, Peck CC (2000) Prediction of the outcome of a phase 3 clinical trial of an antischizophrenic agent (quetiapine fumarate) by simulation with a population pharmacokinetic and pharmacodynamic model. Clin Pharmacol Ther 68(5):568–577PubMedCrossRefGoogle Scholar
  22. 22.
    Friberg LE, de Greef R, Kerbusch T, Karlsson MO (2009) Modeling and simulation of the time course of asenapine exposure response and dropout patterns in acute schizophrenia. Clin Pharmacol Ther 86(1):84–91. doi:clpt200944 PubMedCrossRefGoogle Scholar
  23. 23.
    Wong KS, Li H, Lam WWM, Chan YL, Kay R (2002) Progression of middle cerebral artery occlusive disease and its relationship with further vascular events after stroke. Stroke 33(2):532–536. doi:10.1161/hs0202.102602 PubMedCrossRefGoogle Scholar
  24. 24.
    Chan PL, Holford NH (2001) Drug treatment effects on disease progression. Annu Rev Pharmacol Toxicol 41:625–659. doi:10.1146/annurev.pharmtox.41.1.625 PubMedCrossRefGoogle Scholar
  25. 25.
    Bock RW, Gray-Weale AC, Mock PA, Robinson DA, Irwig L, Lusby RJ (1993) The natural history of asymptomatic carotid artery disease. J Vasc Surg 17(1):160–171. doi:10.1016/0741-5214(93)90020-m PubMedCrossRefGoogle Scholar
  26. 26.
    Karlsson KE, Wilkins JJ, Jonsson F, Zingmark PH, Karlsson MO, Jonsson EN (2010) Modeling disease progression in acute stroke using clinical assessment scales. AAPS J 12(4):683–691. doi:10.1208/s12248-010-9230-0 PubMedCrossRefGoogle Scholar
  27. 27.
    Stinear CM, Barber PA, Petoe M, Anwar S, Byblow WD (2012) The PREP algorithm predicts potential for upper limb recovery after stroke. Brain 135(8):2527–2535. doi:10.1093/brain/aws146 PubMedCrossRefGoogle Scholar
  28. 28.
    Vu TC, Nutt JG, Holford NHG (2012) Disease progress and response to treatment as predictors of survival, disability, cognitive impairment and depression in Parkinson’s disease. Br J Clin Pharmacol 74(2):284–295. doi:10.1111/j.1365-2125.2012.04208.x PubMedCrossRefGoogle Scholar
  29. 29.
    Yesavage JA, Poulsen SL, Sheikh J, Tanke E (1988) Rates of change of common measures of impairment in senile dementia of the Alzheimer’s type. Psychopharmacol Bull 24(4):531–534PubMedGoogle Scholar
  30. 30.
    Holford NH, Peace K (1994) The effect of tacrine and lecithin in Alzheimer’s disease. A population pharmacodynamic analysis of five clinical trials. Eur J Clin Pharmacol 47(1):17–23PubMedGoogle Scholar
  31. 31.
    Holford NH, Peace KE (1992) Results and validation of a population pharmacodynamic model for cognitive effects in Alzheimer patients treated with tacrine. Proc Natl Acad Sci USA 89(23):11471–11475PubMedCrossRefGoogle Scholar
  32. 32.
    Ito K, Ahadieh S, Corrigan B, French J, Fullerton T, Tensfeldt T (2010) Disease progression meta-analysis model in Alzheimer’s disease. Alzheimers Dement 6:39–53. doi:10.1016/j.jalz.2009.05.665 PubMedCrossRefGoogle Scholar
  33. 33.
    Rogers J, Polhamus D, Gillespie W, Ito K, Romero K, Qiu R, Stephenson D, Gastonguay M, Corrigan B (2012) Combining patient-level and summary-level data for Alzheimer’s disease modeling and simulation: a beta regression meta-analysis. J Pharmacokinet Pharmacodyn 39(5):478–498. doi:10.1007/s10928-012-9263-3 CrossRefGoogle Scholar
  34. 34.
    Ueckert S, Plan EL, Ito K, Karlsson MO, Corrigan B, Hooker AC (2012) Application of item response theory to ADAS-cog scores modelling in Alzheimer’s disease (Abstr 2318), p 21. www.page-meeting.org/?abstract=2318. Accessed 12 April 2013
  35. 35.
    Samtani MN, Farnum M, Lobanov V, Yang E, Raghavan N, DiBernardo A, Narayan V, Initiative AsDN (2012) An improved model for disease progression in patients from the Alzheimer’s disease neuroimaging initiative. J Clin Pharmacol 52(5):629–644. doi:10.1177/0091270011405497 PubMedCrossRefGoogle Scholar
  36. 36.
    Galimberti D, Scarpini E (2011) Disease-modifying treatments for Alzheimer’s disease. Ther Adv Neurol Disord 4(4):203–216. doi:10.1177/1756285611404470 PubMedCrossRefGoogle Scholar
  37. 37.
    Salomone S, Caraci F, Leggio GM, Fedotova J, Drago F (2012) New pharmacological strategies for treatment of Alzheimer’s disease: focus on disease modifying drugs. Br J Clin Pharmacol 73(4):504–517. doi:10.1111/j.1365-2125.2011.04134.x PubMedCrossRefGoogle Scholar
  38. 38.
    Holford NH, Chan PL, Nutt JG, Kieburtz K, Shoulson I (2006) Disease progression and pharmacodynamics in Parkinson disease—evidence for functional protection with levodopa and other treatments. J Pharmacokinet Pharmacodyn 33(3):281–311. doi:10.1007/s10928-006-9012-6 PubMedCrossRefGoogle Scholar
  39. 39.
    Bhattaram VA, Siddiqui O, Kapcala LP, Gobburu JV (2009) Endpoints and analyses to discern disease-modifying drug effects in early Parkinson’s disease. AAPS J 11(3):456–464. doi:10.1208/s12248-009-9123-2 PubMedCrossRefGoogle Scholar
  40. 40.
    Chan PL, Nutt JG, Holford NH (2005) Pharmacokinetic and pharmacodynamic changes during the first four years of levodopa treatment in Parkinson’s disease. J Pharmacokinet Pharmacodyn 32(3–4):459–484PubMedCrossRefGoogle Scholar
  41. 41.
    Lee JY, Gobburu JV (2011) Bayesian quantitative disease-drug-trial models for Parkinson’s disease to guide early drug development. AAPS J 13(4):508–518. doi:10.1208/s12248-011-9293-6 PubMedCrossRefGoogle Scholar
  42. 42.
    Hauser RA, Lew MF, Hurtig HI, Ondo WG, Wojcieszek J, Fitzer-Attas CJ (2009) Long-term outcome of early versus delayed rasagiline treatment in early Parkinson’s disease. Mov Disord 24(4):564–573. doi:10.1002/mds.22402 PubMedCrossRefGoogle Scholar
  43. 43.
    The Parkinson Study Group (2004) Levodopa and the progression of Parkinson’s disease. N Engl J Med 351(24):2498–2508CrossRefGoogle Scholar
  44. 44.
    Ma SC, Holford NHG (2011) Quantifying disease progress with inactive treatments in multiple Parkinson’s disease trials. http://wwwpaganzorg/defaultasp?abstract=1143. Accessed 12 April 2013
  45. 45.
    Fahn S (1999) Parkinson disease, the effect of levodopa, and the ELLDOPA trial. Earlier vs Later L-DOPA. Arch Neurol 56(5):529–535PubMedCrossRefGoogle Scholar
  46. 46.
    Hauser RA, Holford NH (2002) Quantitative description of loss of clinical benefit following withdrawal of levodopa-carbidopa and bromocriptine in early Parkinson’s disease. Mov Disord 17(5):961–968. doi:10.1002/mds.10226 PubMedCrossRefGoogle Scholar
  47. 47.
    Chan PL, Nutt JG, Holford NH (2007) Levodopa slows progression of Parkinson’s disease: external validation by clinical trial simulation. Pharm Res 24(4):791–802. doi:10.1007/s11095-006-9202-3 PubMedCrossRefGoogle Scholar
  48. 48.
    Ploeger B, Holford NHG (2011) Confirmation of symptomatic and disease modifying effects of levodopa using the ELLDOPA study (Abstr 2145), p 20. www.page-meeting.org/?abstract=2145. Accessed 12 April 2013
  49. 49.
    Olanow CW, Rascol O, Hauser R, Feigin PD, Jankovic J, Lang A, Langston W, Melamed E, Poewe W, Stocchi F, Tolosa E (2009) A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med 361(13):1268–1278. doi:361/13/1268 PubMedCrossRefGoogle Scholar
  50. 50.
    Ploeger BA, Holford NH (2009) Washout and delayed start designs for identifying disease modifying effects in slowly progressive diseases using disease progression analysis. Pharm Stat 8(3):225–238. doi:10.1002/pst.355 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Pharmacology & Clinical PharmacologyUniversity of AucklandAucklandNew Zealand

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