Robert H Wichers1,2, James L Findon3, Auke Jelsma3,4, Vincent Giampietro5, Vladimira Stoencheva6, Dene M Robertson3,6, Clodagh M Murphy3,6, Sarah Blainey3, Grainne McAlonan3,6, Christine Ecker7, Katya Rubia8, Declan G M Murphy3,6, Eileen M Daly3. 1. Department of Forensic and Neurodevelopmental Sciences, The Sackler Centre for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, PO50 De Crespigny Park, Denmark Hill, London, SE5 8AF, UK. rob.wichers@kcl.ac.uk. 2. Behavioural and Developmental Psychiatry Clinical Academic Group, South London and Maudsley NHS Trust, London, UK. rob.wichers@kcl.ac.uk. 3. Department of Forensic and Neurodevelopmental Sciences, The Sackler Centre for Translational Neurodevelopment, Institute of Psychiatry, Psychology and Neuroscience, King's College London, PO50 De Crespigny Park, Denmark Hill, London, SE5 8AF, UK. 4. VU University Medical Center, Amsterdam, The Netherlands. 5. Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. 6. Behavioural and Developmental Psychiatry Clinical Academic Group, South London and Maudsley NHS Trust, London, UK. 7. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt am Main, Goethe-University, Frankfurt am Main, Germany. 8. Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Abstract
BACKGROUND: Autism spectrum disorder (ASD) is associated with deficits in executive functioning (EF), and these have been suggested to contribute to core as well as co-occurring psychiatric symptoms. The biological basis of these deficits is unknown but may include the serotonergic system, which is involved both in regulating EF in neurotypical populations and in the pathophysiology of ASD. We previously demonstrated that reducing serotonin by acute tryptophan depletion (ATD) shifts differences in brain function during performance of EF tasks towards control levels. However, ATD cannot be easily used in the clinic, and we therefore need to adopt alternative approaches to challenge the serotonin system. Hence, we investigated the role of the serotonergic modulator tianeptine on EF networks in ASD. METHOD: We conducted a pharmacological magnetic resonance imaging study, using a randomized double-blind crossover design, to compare the effect of an acute dosage of 12.5 mg tianeptine and placebo on brain activation during two EF tasks (of response inhibition and sustained attention) in 38 adult males: 19 with ASD and 19 matched controls. RESULTS: Under placebo, compared to controls, individuals with ASD had atypical brain activation in response inhibition regions including the inferior frontal cortex, premotor regions and cerebellum. During sustained attention, individuals with ASD had decreased brain activation in the right middle temporal cortex, right cuneus and left precuneus. Most of the case-control differences in brain function observed under placebo conditions were abolished by tianeptine administration. Also, within ASD individuals, brain functional differences were shifted significantly towards control levels during response inhibition in the inferior frontal and premotor cortices. LIMITATIONS: We conducted a pilot study using a single dose of tianeptine, and therefore, we cannot comment on long-term outcome. CONCLUSIONS: Our findings provide the first evidence that tianeptine can shift atypical brain activation during EF in adults with ASD towards control levels. Future studies should investigate whether this shift in the biology of ASD is maintained after prolonged treatment with tianeptine and whether it improves clinical symptoms.
BACKGROUND: Autism spectrum disorder (ASD) is associated with deficits in executive functioning (EF), and these have been suggested to contribute to core as well as co-occurring psychiatric symptoms. The biological basis of these deficits is unknown but may include the serotonergic system, which is involved both in regulating EF in neurotypical populations and in the pathophysiology of ASD. We previously demonstrated that reducing serotonin by acute tryptophan depletion (ATD) shifts differences in brain function during performance of EF tasks towards control levels. However, ATD cannot be easily used in the clinic, and we therefore need to adopt alternative approaches to challenge the serotonin system. Hence, we investigated the role of the serotonergic modulator tianeptine on EF networks in ASD. METHOD: We conducted a pharmacological magnetic resonance imaging study, using a randomized double-blind crossover design, to compare the effect of an acute dosage of 12.5 mg tianeptine and placebo on brain activation during two EF tasks (of response inhibition and sustained attention) in 38 adult males: 19 with ASD and 19 matched controls. RESULTS: Under placebo, compared to controls, individuals with ASD had atypical brain activation in response inhibition regions including the inferior frontal cortex, premotor regions and cerebellum. During sustained attention, individuals with ASD had decreased brain activation in the right middle temporal cortex, right cuneus and left precuneus. Most of the case-control differences in brain function observed under placebo conditions were abolished by tianeptine administration. Also, within ASD individuals, brain functional differences were shifted significantly towards control levels during response inhibition in the inferior frontal and premotor cortices. LIMITATIONS: We conducted a pilot study using a single dose of tianeptine, and therefore, we cannot comment on long-term outcome. CONCLUSIONS: Our findings provide the first evidence that tianeptine can shift atypical brain activation during EF in adults with ASD towards control levels. Future studies should investigate whether this shift in the biology of ASD is maintained after prolonged treatment with tianeptine and whether it improves clinical symptoms.
Authors: Oliver D Howes; Maria Rogdaki; James L Findon; Robert H Wichers; Tony Charman; Bryan H King; Eva Loth; Gráinne M McAlonan; James T McCracken; Jeremy R Parr; Carol Povey; Paramala Santosh; Simon Wallace; Emily Simonoff; Declan G Murphy Journal: J Psychopharmacol Date: 2017-12-14 Impact factor: 4.153
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Authors: Deborah L Christensen; Jon Baio; Kim Van Naarden Braun; Deborah Bilder; Jane Charles; John N Constantino; Julie Daniels; Maureen S Durkin; Robert T Fitzgerald; Margaret Kurzius-Spencer; Li-Ching Lee; Sydney Pettygrove; Cordelia Robinson; Eldon Schulz; Chris Wells; Martha S Wingate; Walter Zahorodny; Marshalyn Yeargin-Allsopp Journal: MMWR Surveill Summ Date: 2016-04-01