, Volume 100, Issue 1, pp 90–97 | Cite as

Age-related increase in CNS sensitivity to benzodiazepines as assessed by task difficulty

  • Arlene M. Nikaido
  • Everett H. EllinwoodJr.
  • Douglas G. Heatherly
  • Samir K. Gupta
Original Investigations


The differential sensitivity of young and elderly healthy adults to the impairment effects of benzodiazepines was assessed by tasks with several levels of difficulty. Using a double-blind procedure, single doses of placebo, alprazolam (0.75 and 1.5 mg) and triazolam (0.25 and 0.5 mg) were ingested orally by 10 young men, 9 young women, 7 elderly men, and 10 elderly women. Order of drug administration was determined by a random Latin square design. Different versions of the subcritical tracking and digit symbol substitution tasks were characterized by three difficulty levels. Assessments of task performance were conducted at varying intervals for 7 h after drug administration. Both drugs induced a rapid initial onset of impairment in the two age groups. Evidence of increased drug sensitivity in the elderly was provided by the more prolonged duration of the pharmacologic effect in the older than young subjects, especially for the harder versions of the SCT and DSS tasks. In summary, the data provide support for the hypothesis of an age-related decline in the adaptive capacity to inhibit adverse drug effects.

Key words

Alprazolam Triazolam Age differences Task difficulty 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Balter MB, Levine J, Manheimer D (1974) Cross-national study of the extent of anti-anxiety sedative drug use. N Engl J Med 290:766–774CrossRefGoogle Scholar
  2. Boston Collaborative Drug Surveillance Program (1973) Clinical depression of the central nervous system due to diazepam and chlordiazepoxide in relation to cigarette smoking and age. N Engl J Med 288:277–280CrossRefGoogle Scholar
  3. Braestrup C, Nielsen M (1983) Benzodiazepine receptors. In: Iversen LL, Iversen SD, Snyder SH (eds) Handbook of psychopharmacology: biochemical studies of CNS receptors, vol 17. Plenum Press, New York, pp 285–383Google Scholar
  4. Castleden CM, George CF, Marcer D, Hallett C (1977) Increased sensitivity to nitrazepam in old age. Br Med J 1:10–12PubMedCrossRefGoogle Scholar
  5. Cook PJ, Flanagan R, James IM (1984) Diazepam tolerance: effect of age, regular sedation, and alcohol. Br Med J 289:351–353CrossRefGoogle Scholar
  6. Ellinwood EH Jr, Nikaido AM (1987) Perceptual-neuromotor pharmacodynamics of psychotropic drugs. In: Meltzer HY (ed) Pharmacology: the third generation of progress. Raven Press, New York, pp 1457–1466Google Scholar
  7. Ellinwood EH Jr, Linnoila M, Easler ME, Molter DW (1983) Profile of acute tolerance to three sedative-anxiolytics. Psychopharmacology 79:137–141PubMedCrossRefGoogle Scholar
  8. Evans SH, Anastasio EJ (1968) Misuse of analysis of covariance when treatment effect and covariate are confounded. Psychol Bull 69:225–234PubMedCrossRefGoogle Scholar
  9. Giles HG, MacLeod SM, Wright JR, Sellers EM (1978) Influence of age and previous use on diazepam dosage required for endoscopy. Can Med Assoc J 118:513–514PubMedGoogle Scholar
  10. Gilmore G, Royer FL, Gruhn JJ (1983) Age differences in symboldigit substitution. J Clin Psychol 39:114–124PubMedCrossRefGoogle Scholar
  11. Greenblatt DJ, Divoll M, Abernethy DR, Moschitto LJ, Smith RB, Shader RI (1983a) Alprazolam kinetics in the elderly: relation to antipyrine disposition. Arch Gen Psychiatry 40:287–290PubMedGoogle Scholar
  12. Greenblatt DJ, Divoll M, Abernethy DR, Moschitto LJ, Smith RB, Shader RI (1983b) Reduced clearance of triazolam in old age: relation to antipyrine oxidizing capacity. Br J Clin Pharmacol 15:303–309PubMedGoogle Scholar
  13. Kaplan SA, Jack ML (1983) Metabolism of the benzodiazepines: pharmacokinetic and pharmacodynamic considerations. In: Costa E (ed) Benzodiazepines: from molecular biology to clinical practice. Raven Press, New York, pp 173–199Google Scholar
  14. Keppel G (1982) Design and analysis: a researcher's handbook, 2nd ed. Prentice Hall, Englewood CliffsGoogle Scholar
  15. Lader M (1979) Correlation of plasma concentrations of benzodiazepines with clinical effects. In: Priest RG, Pletscher A, Ward J (eds) Sleep research. University Park Press, Baltimore, pp 99–108Google Scholar
  16. MacLeod SM, Giles HG, Patzalek G, Thiessen JJ, Sellers EM (1977) Diazepam actions and plasma concentrations following ethanol ingestion. Eur J Clin Pharmacol 11:345–349PubMedCrossRefGoogle Scholar
  17. Nikaido AM, Ellinwood EH Jr, Heatherly DG, Dubow D (1987) Differential CNS effects of diazepam in elderly adults. Pharmacol Biochem Behav 27:273–281PubMedCrossRefGoogle Scholar
  18. Pomara N, Stanley B, Block R, Guido J, Russ D, Berchou R, Stanley M, Greenblatt DJ, Newton RE, Gershon S (1984) Adverse effects of single therapeutic doses of diazepam on performance in normal geriatric subjects: relationship to plasma concentrations. Psychopharmacology 84:342–346PubMedCrossRefGoogle Scholar
  19. Pomara N, Stanley B, Block R, Berchou RC, Stanley M, Greenblatt DJ, Newton RE, Gershon S (1985) Increased sensitivity of the elderly to the central depressant effects of diazepam. J Clin Psychiatry 46:185–187PubMedGoogle Scholar
  20. Reidenberg MM, Levy M, Warner H, Coutinho CB, Schwartz MA, Yu G, Cheripko J (1978) Relationship between diazepam dose, plasma level, age and central nervous system depression. Clin Pharmacol Ther 23:371–374PubMedGoogle Scholar
  21. Royer FL, Gilmore GC, Gruhn JJ (1981) Normative data for the symbol digit substitution task. J Clin Psychol 37:608–614PubMedCrossRefGoogle Scholar
  22. Salthouse TA (1978) The role of memory in the age decline in digit-symbol substitution performance. J Gerontol 33:232–238PubMedGoogle Scholar
  23. Salthouse TA (1982) Adult cognition. Springer, New York Berlin HeidelbergGoogle Scholar
  24. SAS Institute (1982) SAS user's guide: Statistics. SAS Institute, Cary, NCGoogle Scholar
  25. Stephens RC, Haney CA, Underwood S (1982) Drug taking among the elderly. In: National Institute on Drug Abuse treatment research report and monograph series, DHHS Publication No. ADM 83-1229. U.S. Government Printing Office, Washington, DC, pp 7–25Google Scholar
  26. Storandt M, Hudson W (1975) Misuse of analysis of covariance in aging research and some partial solutions. Exp Aging Res 1:121–125PubMedCrossRefGoogle Scholar
  27. Swift CG, Stevenson IH (1983) Benzodiazepines in the elderly. In: Costa E (ed) The benzodiazepines: from molecular biology to clinical practice. Raven Press, New York, pp 225–236Google Scholar
  28. Wechsler D (1981) Wechsler Adult Intelligence Scale-revised manual. The Psychological Corporation, ClevelandGoogle Scholar
  29. Ziegler G, Ludwig L, Klotz U (1983) Relationships between plasma levels and psychological effects of benzodiazepines. Pharmacopsychiatry 16:71–76CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • Arlene M. Nikaido
    • 1
  • Everett H. EllinwoodJr.
    • 1
  • Douglas G. Heatherly
    • 1
  • Samir K. Gupta
    • 1
  1. 1.Behavioral Neuropharmacology Laboratory, Department of PsychiatryDuke University Medical CenterDurhamUSA

Personalised recommendations