Hostname: page-component-8448b6f56d-m8qmq Total loading time: 0 Render date: 2024-04-19T21:21:31.944Z Has data issue: false hasContentIssue false
  • English
  • Français

Effect of the monoaminergic stabiliser (−)-OSU6162 on mental fatigue following stroke or traumatic brain injury

Published online by Cambridge University Press:  18 May 2020

Marie K.L. Nilsson Open the ORCID record for Marie K.L. Nilsson [Opens in a new window] ,
Birgitta Johansson ,
Maria L. Carlsson ,
Robert C. Schuit  and
Lars Rönnbäck
Marie K.L. Nilsson*
Affiliation:
Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Birgitta Johansson
Affiliation:
Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Maria L. Carlsson
Affiliation:
Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Robert C. Schuit
Affiliation:
Department of Radiology and Nuclear Medicine, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands
Lars Rönnbäck
Affiliation:
Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
*
Author for correspondence: Marie K.L. Nilsson, Email: marie.nilsson@gu.se
Get access Rights & Permissions [Opens in a new window]

Abstract

Objective:

The purpose of the present study was to evaluate the efficacy and safety of (−)-OSU6162 in doses up to 30 mg b.i.d. in patients suffering from mental fatigue following stroke or traumatic brain injury (TBI).

Methods:

This 4 + 4 weeks double-blind randomised cross-over study included 30 patients afflicted with mental fatigue following a stroke or head trauma occurring at least 12 months earlier. Efficacy was assessed using the Mental Fatigue Scale (MFS), the Self-rating Scale for Affective Syndromes [Comprehensive Psychopathological Rating Scale (CPRS)], the Frenchay Activity Index (FAI), and a battery of neuropsychological tests. Safety was evaluated by recording spontaneously reported adverse events (AEs).

Results:

There were significant differences on the patients’ total FAI scores (p = 0.0097), the subscale FAI outdoor scores (p = 0.0243), and on the trail making test (TMT-B) (p = 0.0325) in favour of (−)-OSU6162 treatment. Principal component analysis showed a clear overall positive treatment effect in 10 of 28 patients; those who responded best to treatment had their greatest improvements on the MFS. Reported AEs were mild or moderate in severity and did not differ between the (−)-OSU6162 and the placebo period.

Conclusion:

The most obvious beneficial effects of (−)-OSU6162 were on the patients’ activity level, illustrated by the improvement on the FAI scale. Moreover, a subgroup of patients showed substantial improvements on the MFS. Based on these observed therapeutic effects, in conjunction with the good tolerability of (−)-OSU6162, this compound may offer promise for treating at least part of the symptomatology in patients suffering from stroke- or TBI-induced mental fatigue.

Keywords

drug therapybrain injuriesstrokemental fatiguelife quality
Type
Original Article
Information
Acta Neuropsychiatrica , Volume 32 , Issue 6 , December 2020 , pp. 303 - 312
Copyright
© Scandinavian College of Neuropsychopharmacology 2020

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

In memory of Nobel Prize Winner Arvid Carlsson and senior doctor Elisabeth Nordquist Brandt, MD. Arvid Carlsson devoted his last 10 years almost entirely to the further exploration and development of (−)-OSU6162, which included this and other clinical studies as well as preclinical research. Elisabeth Nordquist Brandt was deeply engaged in the clinical development of (−)-OSU6162; in the present study, she was responsible for the clinical aspects involving the stroke patients.

References

Altman, GA (1991) Practical Statistics for Medical Reserch. London: Chapman & Hall. Google Scholar
Asberg, M, Montgomery, SA, Perris, C, Schalling, D and Sedvall, G (1978) A comprehensive psychopathological rating scale. Acta Psychiatrica Scandinavica Supplement, Suppl 271, 5–27.CrossRefGoogle ScholarPubMed
Brennan, AR and Arnsten, AF (2008) Neuronal mechanisms underlying attention deficit hyperactivity disorder: the influence of arousal on prefrontal cortical function. Annals of the New York Academy of Sciences 1129, 236–245.CrossRefGoogle ScholarPubMed
Brioschi, A, Gramigna, S, Werth, E, Staub, F, Ruffieux, C, Bassetti, C, Schluep, M and Annoni, JM (2009) Effect of modafinil on subjective fatigue in multiple sclerosis and stroke patients. European Neurological 62, 243–249.CrossRefGoogle ScholarPubMed
Burstein, ES, Carlsson, ML, Owens, M, Ma, JN, Schiffer, HH, Carlsson, A and Hacksell, U (2011) II. In vitro evidence that (−)-OSU6162 and (+)-OSU6162 produce their behavioral effects through 5-HT2A serotonin and D2 dopamine receptors. Journal of Neural Transmission 118, 1523–1533.CrossRefGoogle ScholarPubMed
Cantor, JB, Gordon, W and Gumber, S (2013) What is post TBI fatigue? NeuroRehabilitation 32, 875–883.CrossRefGoogle ScholarPubMed
Carlsson, ML, Burstein, ES, Kloberg, A, Hansson, S, Schedwin, A, Nilsson, M, Rung, JP and Carlsson, A (2011) I. In vivo evidence for partial agonist effects of (−)-OSU6162 and (+)-OSU6162 on 5-HT2A serotonin receptors. Journal of Neural Transmission 118, 1511–1522.CrossRefGoogle ScholarPubMed
Carlsson, ML, Carlsson, A and Nilsson, M (2004) Schizophrenia: from dopamine to glutamate and back. Current Medicinal Chemistry 11, 267–277.CrossRefGoogle Scholar
Chaudhuri, A and Behan, PO (2004) Fatigue in neurological disorders. Lancet 363, 978–988.CrossRefGoogle ScholarPubMed
Deluca, J (2005) Fatigue as a Window to the Brain. London: The MIT Press.CrossRefGoogle Scholar
Ellis, D, Kaplane, E and Kramer, JH (2001) Delis-Kaplan Executive Function System – D-KEFS. San Antonio, TX: The Psychological Corporation.Google Scholar
Gefvert, O, Lindström, LH, Dahlbäck, O, Sonesson, C, Waters, N, Carlsson, A and Tedroff, J (2000) (−)-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. Nordic Journal of Psychiatry, 93–94.Google Scholar
Glader, EL, Stegmayr, B and Asplund, K (2002) Poststroke fatigue: a 2-year follow-up study of stroke patients in Sweden. Stroke 33, 1327–1333.CrossRefGoogle ScholarPubMed
Hodges, JL Jr and Lehmann, EL (1983) Hodges-lehmann estimators. In: Kotz, S, Johnson, NL and Read, CB (eds), Encyclopedia of Statistical Sciences. New York: John Wiley & Sons.Google Scholar
Holbrook, M and Skilbeck, CE (1983) An activities index for use with stroke patients. Age Ageing 12, 166–170.CrossRefGoogle ScholarPubMed
Hollander, M and Wolfe, DA (1999) Nonparametric Statistical Methods. New York: John Wiley & Sons.Google Scholar
Jha, A, Weintraub, A, Allshouse, A, Morey, C, Cusick, C, Kittelson, J, Harrison-Felix, C, Whiteneck, G and Gerber, D (2008) A randomized trial of modafinil for the treatment of fatigue and excessive daytime sleepiness in individuals with chronic traumatic brain injury. Journal of Head Trauma Rehabilitation 23, 52–63.CrossRefGoogle ScholarPubMed
Johansson, B, Berglund, P and Ronnback, L (2009) Mental fatigue and impaired information processing after mild and moderate traumatic brain injury. Brain Injury 23, 1027–1040.CrossRefGoogle ScholarPubMed
Johansson, B, Carlsson, A, Carlsson, ML, Karlsson, M, Nilsson, MK, Nordquist-Brandt, E and Ronnback, L (2012) Placebo-controlled cross-over study of the monoaminergic stabiliser (−)-OSU6162 in mental fatigue following stroke or traumatic brain injury. Acta Neuropsychiatrica 24, 266–274.CrossRefGoogle ScholarPubMed
Johansson, B and Ronnback, L (2014) Evaluation of the mental fatigue scale and its relation to cognitive and emotional functioning after traumatic brain injury or stroke. International Journal of Physical Medicine & Rehabilitation 2, 2–7.Google Scholar
Johansson, B and Ronnback, L (2015) Novel computer tests for identification of mental fatigue after traumatic brain injury. NeuroRehabilitation 36, 195–202.CrossRefGoogle ScholarPubMed
Johansson, B, Starmark, A, Berglund, P, Rodholm, M and Ronnback, L (2010) A self-assessment questionnaire for mental fatigue and related symptoms after neurological disorders and injuries. Brain Injury 24, 2–12.CrossRefGoogle ScholarPubMed
Johansson, B, Wentzel, AP, Andrell, P, Odenstedt, J, Mannheimer, C and Ronnback, L (2014) Evaluation of dosage, safety and effects of methylphenidate on post-traumatic brain injury symptoms with a focus on mental fatigue and pain. Brain Injury 28, 304–310.CrossRefGoogle ScholarPubMed
Kaiser, PR, Valko, PO, Werth, E, Thomann, J, Meier, J, Stocker, R, Bassetti, CL and Baumann, CR (2010) Modafinil ameliorates excessive daytime sleepiness after traumatic brain injury. Neurology 75, 1780–1785.CrossRefGoogle ScholarPubMed
Kloberg, A, Constantinescu, R, Nilsson, MK, Carlsson, ML, Carlsson, A, Wahlstrom, J and Haghighi, S (2014) Tolerability and efficacy of the monoaminergic stabilizer (−)-OSU6162 (PNU-96391A) in Huntington’s disease: a double-blind cross-over study. Acta Neuropsychiatrica 26, 298–306.CrossRefGoogle ScholarPubMed
Lahti, RA, Tamminga, CA and Carlsson, A (2007) Stimulating and inhibitory effects of the dopamine “stabilizer” (−)-OSU6162 on dopamine D2 receptor function in vitro. Journal of Neural Transmission 114, 1143–1146.CrossRefGoogle ScholarPubMed
Lundberg, T, Tedroff, J, Waters, N, Sonesson, C and Carlsson, A (2002) Safety of early clinical experience with (−)-OSU6162, a dopaminergic stabilizer with antipsychotic properties. SCNP 43rd Annual and 2nd Mediterranean Meeting, Juan-les-Pins, France. Nordic Journal of Psychiatry, 24.Google Scholar
Madisons, S (2003) Läsdiagnos. Lund: Läs och skrivcentrum.Google Scholar
Nilsson, MKL, Zachrisson, O, Gottfries, CG, Matousek, M, Peilot, B, Forsmark, S, Schuit, RC, Carlsson, ML, Kloberg, A and Carlsson, A (2018) A randomised controlled trial of the monoaminergic stabiliser (−)-OSU6162 in treatment of myalgic encephalomyelitis/chronic fatigue syndrome. Acta Neuropsychiatrica 30, 148–157.CrossRefGoogle ScholarPubMed
Reitan, RM and Wolfson, D (1985) The Halstead-Reitan Neuropsychological Test Battery, Theory and Clinical Interpretation. Tucson, AZ: Neuropsychology Press.Google Scholar
Rodriguez, CA, Azie, NE, Adams, G, Donaldson, K, Francom, SF, Staton, BA and Bombardt, PA (2004) Single oral dose safety, tolerability, and pharmacokinetics of PNU-96391 in healthy volunteers. Journal of Clinical Pharmacology 44, 276–283.CrossRefGoogle ScholarPubMed
Rung, JP, Rung, E, Helgeson, L, Johansson, AM, Svensson, K, Carlsson, A and Carlsson, ML (2008) Effects of (−)-OSU6162 and ACR16 on motor activity in rats, indicating a unique mechanism of dopaminergic stabilization. Journal of Neural Transmission 115, 899–908.CrossRefGoogle ScholarPubMed
Schuling, J, de Haan, R, Limburg, M and Groenier, KH (1993) The frenchay activities index. Assessment of functional status in stroke patients. Stroke 24, 1173–1177.CrossRefGoogle ScholarPubMed
Svanborg, P and Asberg, M (1994) A new self-rating scale for depression and anxiety states based on the comprehensive psychopathological rating scale. Acta Psychiatrica Scandinavica 89, 21–28.CrossRefGoogle ScholarPubMed
Tolboom, N, Berendse, HW, Leysen, JE, Yaqub, M, van Berckel, BN, Schuit, RC, Ponsen, MM, Bakker, E, Hoetjes, NJ, Windhorst, AD, Carlsson, ML, Lammertsma, AA and Carlsson, A (2015) The dopamine stabilizer (−)-OSU6162 occupies a subpopulation of striatal dopamine D2/D3 receptors: an [(11)C]raclopride PET study in healthy human subjects. Neuropsychopharmacology 40, 472–479.CrossRefGoogle ScholarPubMed
Wechsler, D (2003) WAIS III: Wechsler Adult Intelligence Scale – Third Edition. Swedish Version, 3rd Edn. Stockholm: Pearson Assessment. Google Scholar