R. H. Wichers1,2, J. L. Findon
1,2, A. Jelsma
1,2, V. Giampietro
3, D. Robertson
4, C. M. Murphy
5,6, G. M. McAlonan
2,5, K. Rubia
7, C. Ecker
8, E. Daly
4,5 and D. G. Murphy
5,9, (1)Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom, (2)FANS, The Sackler Institute for Translational Neurodevelopmental Sciences, IoPPN, King's College London, London, United Kingdom, London, United Kingdom, (3)Department of Neuroimaging, The Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom, (4)Sackler Institute for Translational Neurodevelopment and Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom, (5)Department of Forensic and Neurodevelopmental Sciences, and the Sackler Institute for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom, (6)Behavioural Genetics Clinic, Adult Autism Service, Behavioural and Developmental Psychiatry Clinical Academic Group, South London and Maudsley Foundation NHS Trust, London, United Kingdom, (7)Department of Child & Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom, (8)Department of Child and Adolescent Psychiatry, Psychosomatics and Psychiatry, Goethe-University Frankfurt am Main, Frankfurt, Germany, (9)Forensic and Neurodevelopmental Sciences, The Sackler Institute for Translational Neurodevelopmental Sciences, IoPPN, King's College London, London, United Kingdom, London, United Kingdom
Background: Prior research has demonstrated abnormal brain activation during sustained attention in individuals with autism spectrum disorder (ASD). The neurobiological basis for this is unknown but the serotonergic system may play a key role. For example, hyperserotonemia has been frequently reported in ASD; and we demonstrated that reducing serotonin by acute tryptophan depletion (ATD) modulates abnormalities in brain function. However, ATD cannot be easily used in clinical settings. Hence, investigating the modulating role of an existing drug that reduces serotonin may shed light on a novel treatment opportunity with the potential to be rapidly translated into the clinic.
Objectives: To test the effect of the selective serotonin reuptake enhancer (SSRE), tianeptine, on sustained attention networks in ASD.
Methods: We included 19 right-handed adult males with ASD (diagnosed using the ADI-R and ADOS) and 19 age- and IQ- matched control subjects. Pharmacological magnetic resonance imaging (phMRI) was used to compare brain activity during a parametrically modulated sustained attention task under an acute dosage of 12.5 mg tianeptine and placebo in a randomised, double blind procedure. The phMRI data were analysed using a nonparametric approach (c.f. http://brainmap.it) and significance was defined as p <.05 (corrected for multiple comparisons).
Results: Individuals with ASD had significantly decreased activation under placebo in regions involved in regulating sustained attention - including right caudate, right thalamus, left precentral gyrus and left middle frontal gyrus. In contrast they had increased activation in left insula and right middle temporal gyrus. After tianeptine administration brain activation in individuals with ASD was modulated towards control placebo levels in brain regions that mediate sustained attention - including right thalamus, right caudate, right middle temporal gyrus, left precentral gyrus, left middle frontal gyrus and left insula.
Conclusions: Our findings provide first evidence that serotonergic modulation with an SSRE can ‘normalise’ brain activation during sustained attention in adults with ASD. This is now being ‘translated’ to the clinic to establish whether tianeptine is an effective symptomatic treatment for some individuals with ASD.
