Skip to main content
×
×
Home

Placebo-controlled cross-over study of the monoaminergic stabiliser (−)-OSU6162 in mental fatigue following stroke or traumatic brain injury

  • Birgitta Johansson (a1), Arvid Carlsson (a1), Maria L. Carlsson (a1), Magdalena Karlsson (a1), Marie K.L. Nilsson (a1), Elisabeth Nordquist-Brandt (a1) and Lars Rönnbäck (a1)...
Extract

Objective: Mental fatigue occurring after a stroke or traumatic brain injury (TBI) often results in difficulties returning to work and pursuing social activities. No effective treatment of this condition is available today. In this study, we have tested a novel pharmacological strategy using the monoaminergic stabiliser (−)-OSU6162.

Methods: (−)-OSU6162 was given orally for 4 weeks in doses increasing from 15 to 45 mg b.i.d. to 12 patients suffering from mental fatigue, following upon stroke (n=6) or TBI (n=6). (−)-OSU6162 was compared with placebo using a double-blind, randomised cross-over design. Patients included were well rehabilitated physically with no gross impairment in cognitive functions other than those related to the mental fatigue.

Results: (−)-OSU6162 caused a remarkable improvement in mental stamina, as evaluated by a self-assessment scale on mental fatigue. Statistical significance was reached on the primary endpoint (Mental Fatigue Scale). There was a trend towards improvement in the secondary endpoints processing speed and attention. Principal component analysis showed an overall positive treatment effect in 7 of 12 patients. Beneficial responses were seen already during the first few days of active drug treatment. Increasing dosage caused no further improvement. Adverse reactions consisted of short-lasting mild nausea and attenuated appetite. These side effects disappeared upon dose reduction.

Conclusion: The monoaminergic stabiliser (−)-OSU6162 offers promise as a candidate for treatment of mental fatigue after a stroke or TBI.

Copyright
Corresponding author
Birgitta Johansson, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Per Dubbsgatan 14, 1tr, SE 413 45 Gothenburg, Sweden. Tel: +46-31-3421000; Fax: +031-3422467; E-mail: birgitta.johansson@neuro.gu.se
References
Hide All
Chaudhuri, A, Behan, PO. Fatigue in neurological disorders. Lancet 2004;363:978988.
Deluca, J. Fatigue as a window to the brain. Cambridge, Massachusetts, London, England: A Bradford Book, The MIT Press, 2005.
Rödholm, M, Starmark, J-E, Svensson, E, Von Essen, C. Asteno-emotional disorder after aneurysmal SAH: reliability, symptomatology and relation to outcome. Acta Neurol Scand 2001;103:379385.
Rönnbäck, L, Hansson, E. On the potential role of glutamate transport in mental fatigue. J Neuroinflammation 2004;1:22.
Lindqvist, G, Malmgren, H. Organic mental disorders as hypothetical pathogenetic processes. Acta Psychiatr Scand 1993;88(Suppl. 373):517.
Staub, F, Bogousslavsky, J. Fatigue after stroke: a major but neglected issue. Cerebrovasc Dis 2001;12:7581.
Belmont, A, Agar, N, Hugeron, C, Gallais, B, Azouvi, P. Fatigue and traumatic brain injury. Ann Readapt Med Phys 2006;49:283288.
Kohl, AD, Wylie, GR, Genova, HM, Hillary, F, Deluca, J. The neural correlates of cognitive fatigue in traumatic brain injury using functional MRI. Brain Inj 2009;23:420432.
Ziino, C, Ponsford, J. Vigilance and fatigue following traumatic brain injury. J Int Neuropsychol Soc 2006;12:100110.
Ashman, TA, Cantor, JB, Gordon, WA et al. Objective measurement of fatigue following traumatic brain injury. J Head Trauma Rehabil 2008;23:3340.
Johansson, B, Berglund, P, Rönnbäck, L. Mental fatigue and impaired information processing after mild and moderate traumatic brain injury. Brain Inj 2009;23(13-14):10271040.
Johansson, B, Rönnbäck, L. Mental fatigue: a common long term consequence after a brain injury. In: Agrawal, A, ed. Brain injury - functional aspects, rehabilitation and prevention. Rijeka, Croatia: InTech, 2012: 316.
Brennan, AR, Arnsten, FT. Neuronal mechanisms underlying attention deficit hyperactivity disorder. Ann N Y Acad Sci 2008;1129:236245.
Posner, IM, Rothbart, MK. Research on attention networks as a model for the integration of psychological science. Annu Rev Psychol 2007;58:123.
Azmitia, EC. Serotonin neurons, neuroplasticity, and homeostasis of neural tissue. Neuropsychopharmacology 1999;21(Suppl. 2):33S45S.
Rung, JP, Rung, E, Helgeson, L et al. Effects of (−)-OSU6162 and ACR16 on motor activity in rats, indicating a unique mechanism of dopaminergic stabilization. J Neural Transm 2008;115:899908.
Lahti, R, Tamminga, CA, Carlsson, A. Stimulating and inhibitory effects of the dopamine stabilizer (−)-OSU6162 on dopamine D(2) receptor function in vitro. J Neural Transm 2007;114:11431146.
Ekesbo, A, Andrén, PE, Gunne, LM, Tedroff, J. (−)-OSU 6162 inhibits levodopa-induced dyskinesias in a monkey model of Parkinson's disease. Neuroreport 1997;8:25672570.
Tedroff, J, Ekesbo, A, Rydin, E, Sonesson, S, Waters, AN, Carlsson, A. Clinical effects of (-)-OSU6162 in very advanced Parkinson's disease. A study report to the Swedish Medical Products Agency, March 9, 2000.
Tedroff, J, Ekesbo, A, Sonesson, S, Waters, N, Carlsson, A. Long-lasting improvement following (−)-OSU6162 in patients with Huntington's disease. Neurology 1999;53:16051606.
Gefvert, O, Lindström, LH, Dahlbäck, O et al. (−)-OSU6162 induces a rapid onset of antipsychotic effect after a single dose. A double-blind placebo-controlled pilot study. Scandinavian Society for Psychopharmacology 41st annual meeting, Copenhagen, Denmark. Nord J Psychiatry 2000;54:9394.
Lundberg, T, Tedroff, J, Waters, N et al. Safety of early clinical experience with (-)-OSU6162, a dopaminergic stabilizer with antipsychotic properties. In: SCNP 43rd Annual and 2nd Mediterranean Meeting, Juan-les-Pins, France. Nord J Psychiatry 2002;56:24.
Burstein, ES, Carlsson, ML, Owens, M et al. II. In vitro evidence that (−)-OSU6162 and (+)-OSU6162 produce their behavioral effects through 5-HT2A serotonin and D2 dopamine receptors. J Neural Transm 2011;118:15231533.
Carlsson, ML, Burstein, ES, Kloberg, A et al. I. In vivo evidence for partial agonist effects of (−)-OSU6162 and (+)-OSU6162 on 5-HT2A serotonin receptors. J Neural Transm 2011;118:15111522.
Rodríguez, CA, Azie, NE, Adams, G et al. Single oral dose safety, tolerability, and pharmacokinetics of PNU-96391 (=OSU6162) in healthy volunteers. J Clin Pharmacol 2004;44:276283.
Johansson, B, Starmark, A, Berglund, P, Rödholm, M, Rönnbäck, L. A self-assessment questionnaire for mental fatigue and related symptoms after neurological disorders and injuries. Brain Inj 2010;24:212.
Rönnbäck, L, Johansson, B. Long-lasting mental fatigue after traumatic brain injury or stroke – a new perspective. Saarbrucken: LAP Lambert Academic Publishing, 2012.
Svanborg, P, asberg, M. A new self-rating scale for depression and anxiety states based on the Comprehensive Psychopathological Rating Scale. Acta Psychiatr Scand 1994;89:2128.
asberg, M, Montgomery, SA, Perris, C, Schalling, D, Sedvall, G. A comprehensive psychopathological rating scale. Acta Psychiatr Scand 1978;271(Suppl):527.
Holbrook, M, Skilbeck, CE. An activity index for use with stroke patients. Age Aging 1983;12:166170.
Wechsler, D. Wechsler Adult Intelligence Scale (WAIS-III). 3rd ednin Swedish Stockholm: Pearson Assessment, 2003.
Ellis, DC, Kaplan, E, Kramer, JH. Delis-Kaplan Executive Function System – D-KEFS. San Antonio, TX: The Psychological Corporation, 2001.
Reitan, RM, Wolfson, D. The Halstead-Reitan neuropsychological test battery. Theory and clinical interpretation. Tucson, AZ: Neuropsychology Press, 1985.
Madison, S. Läsdiagnos. Lund: Läs och skrivcentrum, 2003.
Johansson, B, Rönnbäck, L. Mental fatigue and cognitive impairment after an almost neurological recovered stroke. ISRN Psychiatry 2012. [E-pub ahead of print; DOI: 10.5402/2012/686425].
Senn, S. Cross-over trials in clinical research. 2nd edn. Chichester: Wiley, 2002.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Acta Neuropsychiatrica
  • ISSN: 0924-2708
  • EISSN: 1601-5215
  • URL: /core/journals/acta-neuropsychiatrica
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed