Skip to main content
SpringerLink
Log in

Relative lack of cognitive effects of methylphenidate in elderly male volunteers

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Methylphenidate, a dopaminergic and noradrenergic reuptake inhibitor, has been shown in young, healthy adult volunteers to produce pronounced effects on working memory and sustained attention. We were interested in assessing whether similar improvements could be conferred upon elderly volunteers in order to gain a more complete understanding of the effects of age on monoaminergic manipulations of working memory and attention, as well as to explore the potential for pharmacological intervention in attention and executive dysfunction disorders in this age group.

Objectives

The main aim of the study was to characterise the dose-related effects of methylphenidate on a range of neuropsychological functions in elderly healthy volunteers.

Methods

Sixty healthy elderly adult male volunteers received either a single oral dose of placebo, 20 mg or 40 mg methylphenidate prior to performing a variety of tasks designed to assess memory, attention and executive function. A randomised double-blind, between-subjects design was used.

Results

Methylphenidate had significant cardiovascular and subjective effects. However, unlike in younger volunteers, no significant effects of drug on working memory (spatial span and spatial working memory), response inhibition (stop-signal) or sustained attention (rapid visual information processing) were seen. Subtle effects on latency similar to those in younger volunteers were identified: both doses of methylphenidate resulted in a slowing in response time during set-shifting and decision-making.

Conclusions

The results of this study demonstrate that, in elderly subjects, the cognitive effects of methylphenidate are grossly attenuated and distinct from the profile previously described in younger volunteers. It is suggested that methylphenidate may not be appropriate as a pharmacological intervention in elderly patient groups, such as those reporting age-related cognitive decline.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.

Similar content being viewed by others

References

  • Arnsten AFT, Goldman-Rakic PS (1985) α2-Adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates. Science 230:1273–1276

    CAS  PubMed  Google Scholar 

  • Arnsten AFT, Cai JX, Murphy BL, Goldman-Rakic PS (1994) Dopamine D1 receptor mechanisms in cognitive performance of young adult and aged monkeys. Psychopharmacology 116:143–151

    CAS  PubMed  Google Scholar 

  • Arnsten AFT, Cai JX, Steere JC, Goldman-Rakic PS (1995) Dopamine D2 receptor mechanisms contribute to age-related cognitive decline: the effects of quinpirole on memory and motor performance in monkeys. J Neurosci 15:3429–3439

    Google Scholar 

  • Bond A, Lader M (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol 47:211–218

    Google Scholar 

  • Cai JX, Arnsten AFT (1997) Dose-dependent effects of the dopamine D1 receptor agonists A77636 or SKF81297 on spatial working memory in aged monkeys. J Pharmacol Exp Ther 283:183–189

    Google Scholar 

  • Camicioli R, Lea E, Nutt JG, Sexton G, Oken BS (2001) Methylphenidate increases the motor effects of l-dopa in Parkinson's disease: a pilot study. Clin Neuropharmacol 24:208–213

    Article  CAS  PubMed  Google Scholar 

  • Challman TD, Lipsky JJ (2000) Methylphenidate: its pharmacology and uses. Mayo Clin Proc 75:711–721

    CAS  PubMed  Google Scholar 

  • Deakin JB, Robbins TW, Sahakian BJ (2001) Ageing and conservatism in decision making. J Psychopharmacol 15: A38

    Google Scholar 

  • Elliott R, Sahakian BJ, Matthews K, Bannerjea A, Rimmer J, Robbins TW (1997) Effects of methylphenidate on spatial working memory and planning in healthy young adults. Psychopharmacology 131:196–206

    CAS  PubMed  Google Scholar 

  • Folstein MF, Folstein SE, McHugh PR (1975) "Mini-Mental State": a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198

    CAS  PubMed  Google Scholar 

  • Galynker I, Ieronimo C, Miner C, Rosenblum J, Vilkas N, Rosenthal R (1997) Methylphenidate treatment of negative symptoms in patients with dementia. J Neuropsychiatr Clin Neurosci 9: 231–239

    CAS  Google Scholar 

  • Gatley SJ, Pan D, Chen R, Chaturvedi G, Ding YS (1996) Affinities of methylphenidate derivatives for dopamine, norepinephrine and serotonin transporters. Life Sci 58:231–239

    Article  CAS  PubMed  Google Scholar 

  • Goldman-Rakic PS, Brown RM (1981) Regional changes of monoamines in cerebral cortex and subcortical structures of aging rhesus monkeys. Neuroscience 6:177–187

    CAS  PubMed  Google Scholar 

  • Halliday R, Naylor H, Brandeis D, Callaway E, Yano L, Herzig K (1994) The effect of d-amphetamine, clonidine and yohimbine on human information processing. Psychophysiology 31:331–337

    CAS  PubMed  Google Scholar 

  • Harmer CJ, McTavish SF, Clark L, Goodwin GM, Cowen PJ (2001) Tyrosine depletion attenuates dopamine function in healthy volunteers. Psychopharmacology 154:105–111

    CAS  PubMed  Google Scholar 

  • Howell DC (1997) Statistical methods for psychology, 4th edn. Wadsworth, London

  • Kittur S, Hauser P (1999) Improvement of sleep and behaviour by methylphenidate in Alzheimer's disease. Am J Psychiatry 156:1116–1117

    CAS  PubMed  Google Scholar 

  • Koelega HS (1993) Stimulant drugs and vigilance performance: a review. Psychopharmacology 111:1–6

    CAS  PubMed  Google Scholar 

  • Lavretsky H, Kumar A (2001) Methylphenidate augmentation of citalopram in elderly depressed patients. Am J Geriatr Psychiatry 9:298–303

    Article  CAS  PubMed  Google Scholar 

  • Logan GD (1994) On the ability to inhibit thought and action. In: Dagenbach D, Carr TH (eds) Inhibitory processes in attention, memory and language. Academic Press, San Diego, pp 189–239

  • Logan GD, Schachar RJ, Tannock R (1997) Impulsivity and inhibitory control. Psychol Sci 8: 60–64

    Google Scholar 

  • Logan GD, Schachar RJ, Tannock R (2000) Executive control problems in childhood psychopathology: stop signal studies of attention deficit hyperactivity disorder. In: Monsell S, Driver J (eds) Control of cognitive processes: attention and performance XVIII. MIT Press, Cambridge, Mass., 653–677

    Google Scholar 

  • Luciana M, Collins PF (1997) Dopaminergic modulation of working memory for spatial but not object cues in normal humans. J Cognit Neurosci 9:330–347

    Google Scholar 

  • Luine V, Bowling D, Hearns M (1990) Spatial memory deficits in aged rats: contributions of monoaminergic systems. Brain Res 24:271–278

    Article  Google Scholar 

  • McKetin R, Ward PB, Catts SV, Mattick RP, Bell JR (1999) Changes in auditory selective attention and event-related potentials following oral administration of d-amphetamine in humans. Neuropsychopharmacology 21:380–390

    Article  CAS  PubMed  Google Scholar 

  • McTavish SF, McPherson MH, Harmer CJ, Clark L, Sharp T, Goodwin GM, Cowen PJ (2001) Antidopaminergic effects of dietary tyrosine depletion in healthy subjects and patients with manic illness. Br J Psychiatry 179:356–360

    CAS  PubMed  Google Scholar 

  • Mehta MA, Sahakian BJ, McKenna PJ, Robbins TW (1999) Systemic sulpiride in young adult volunteers simulates the profile of cognitive deficits in Parkinson's disease. Psychopharmacology 146:162–174

    CAS  PubMed  Google Scholar 

  • Mehta MA, Swainson R, Ogilvie AD, Sahakian BJ, Robbins TW (2001) Improved short-term spatial memory but impaired reversal learning following the dopamine D2 agonist bromocriptine in human volunteers. Psychopharmacology 159:10–20

    Google Scholar 

  • Nelson H (1982) National adult reading test manual. Windsor NFER-Nelson, UK

  • Osman A, Kornblum S, Meyer DE (1990) Does motor programming necessitate response execution? J Exp Psychol [Hum Percep Perform] 16:183–198

    Google Scholar 

  • Owen AM, Downes JJ, Sahakian BJ, Polkey CE, Robbins TW (1990) Planning and spatial working memory following frontal lobe lesions in man. Neuropsychologia 28:1021–1034

    CAS  PubMed  Google Scholar 

  • Owen AM, Roberts AC, Hodges JR, Summers BA, Polkey CE, Robbins TW (1993) Contrasting mechanisms of impaired attentional set-shifting in patients with frontal lobe damage or Parkinson's disease. Brain 116:1159–1175

    PubMed  Google Scholar 

  • Owen AM, Sahakian BJ, Semple JM, Polkey CE, Robbins TW (1995) Visuo-spatial short-term recognition memory and learning after temporal lobe excisions, frontal lobe excisions or amygdalo-hippocampectomy in man. Neuropsychologia 13:1–24

    Article  Google Scholar 

  • Park SB, Coull JT, McShane RH, Young AH, Sahakian BJ, Robbins TW, Cowen PJ (1994) Tryptophan depletion in normal volunteers produces selective impairments in learning and memory. Neuropharmacology 33:575–588

    CAS  PubMed  Google Scholar 

  • Prendergast MA, Jackson WJ, Terry AV, Kille NJ, Arneric SP, Decker MW, Buccafusco JJ (1998) Age related differences in distractability and response to methylphenidate in monkeys. Cereb Cortex 8:164–172

    Article  CAS  PubMed  Google Scholar 

  • Rabbitt P, Lowe C (2000) Patterns of cognitive ageing. Psychol Res 63:308–316

    PubMed  Google Scholar 

  • Rahman S, Sahakian BJ, Cardinal RN, Rogers RD, Robbins TW (2001) Decision making and neuropsychiatry. Trends Cognit Sci 5:271–277

    Article  Google Scholar 

  • Rapp PR, Amaral DG (1989) Evidence for task-dependent memory dysfunction in the aged monkey. J Neurosci 9:3568–3576

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  • Rogers RD, Blackshaw AJ, Middleton HC, Matthews K, Hawtin K, Crowley C, Hopwood A, Wallace C, Deakin JFW, Sahakian BJ, Robbins TW (1999) Tryptophan depletion impairs stimulus-reward learning while methylphenidate disrupts attentional control in healthy young adults: implication for the monoaminergic basis of impulsive behaviour. Psychopharmacology 146:482–491

    CAS  PubMed  Google Scholar 

  • Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (2001) Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse 38:32–41

    Article  Google Scholar 

  • Rubia K, Overmeyer S, Taylor E, Brammer M, Williams SC, Simmons A, Andrew C, Bullmore ET (2000) Functional frontalisation with age: mapping neurodevelopmental trajectories with fMRI. Neurosci Biobehav Rev 24:13–19

    Article  CAS  PubMed  Google Scholar 

  • Sahakian BJ, Owen AM (1992) Computerized assessment in neuropsychiatry using CANTAB: discussion paper. J R Soc Med 5:399–402

    Google Scholar 

  • Sahakian BJ, Morris R, Evenden JL, Heald A, Levy R, Philpot M, Robbins TW (1988) A comparative study of visuospatial memory and learning in Alzheimer type dementia and Parkinson's disease. Brain 111:695–718

    PubMed  Google Scholar 

  • Schenk S, Snow S, Horger BA (1991) Pre-exposure to amphetamine but not nicotine sensitizes rats to the motor activating effect of cocaine. Psychopharmacology 103:62–66

    Google Scholar 

  • Solanto MV (1998) Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration. Behav Brain Res 94:127–152

    CAS  PubMed  Google Scholar 

  • Suhara T, Fukuda H, Inoue O, Itoh T, Suzuki K, Yamasaki T, Tateno Y (1991) Age-related changes in human D1 dopamine receptors measured by positron emission tomography. Psychopharmacology 103:41–45

    CAS  PubMed  Google Scholar 

  • Tannock R, Schachar RJ, Carr RP, Chajczyk D, Logan GD (1989) Effects of methylphenidate on inhibitory control in hyperactive children. J Abnorm Child Psychol. 17:473–491

    Google Scholar 

  • Volkow ND, Wang G-J, Fowler JS, Logan J, Angrist B, Hitzemann R, Lieberman J, Pappas N (1997) Effects of methylphenidate on regional brain glucose metabolism in humans: relationship to dopamine D2 receptors. Am J Psychiatry 154:50–55

    CAS  PubMed  Google Scholar 

  • Volkow ND, Wang G-J, Fowler JS, Gatley SJ, Logan J, Ding Y-S, Hitzemann R, Pappas N (1998) Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry 155:1325–1331

    CAS  PubMed  Google Scholar 

  • Volkow ND, Wang G-J, Fowler JS, Logan J, Gerasimov M, Maynard L, Ding Yuo Shin, Gatley SJ, Gifford A, Franceschi D (2001) Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine. J Neurosci 21 (RC121):1–5

    Google Scholar 

  • Wechsler D (1981) Wechsler Adult Intelligence Scale, revised. Psychological Corporation, New York

  • Wenk GL, Pierce DJ, Struble RG, Price DL, Cork LC (1989) Age-related changes in multiple neurotransmitter systems in the monkey brain. Neurobiol Aging 10:11–19

    CAS  PubMed  Google Scholar 

  • West RL (1996) An application of prefrontal cortex function theory to cognitive aging. Psychol Bull 120:272–292

    CAS  PubMed  Google Scholar 

  • Zahrt J, Taylor JR, Matthew RG, Arnsten AFT (1997) Supranormal stimulation of D1 dopamine receptors in the rodent prefrontal cortex impairs spatial working memory performance. J Neurosci 17:8528–8535

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the volunteers for participating in this study, which was funded by a Wellcome Trust Programme grant awarded to Professors T.W. Robbins, B.J. Everitt and B.J. Sahakian and Dr. A.C. Roberts and completed within the MRC Centre for Behavioural and Clinical Neuroscience. D.C.T. was funded by a MRC Research Studentship. The stop-signal task was developed under a Stroke Association grant to Professors Stephen Monsell and Ian Robertson.

Author information

Authors and Affiliations

  1. Department of Psychiatry, University of Cambridge, School of Clinical Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ, UK

    Danielle C. Turner, Adam R. Aron, Jonathan Dowson & Barbara J Sahakian

  2. Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge, CB2 3EB, UK

    Trevor W. Robbins & Luke Clark

Authors
  1. Danielle C. Turner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Trevor W. Robbins
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Luke Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Adam R. Aron
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jonathan Dowson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Barbara J Sahakian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Barbara J Sahakian.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Turner, D.C., Robbins, T.W., Clark, L. et al. Relative lack of cognitive effects of methylphenidate in elderly male volunteers. Psychopharmacology 168, 455–464 (2003). https://doi.org/10.1007/s00213-003-1457-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-003-1457-3

Keywords

Search

Navigation