Inverse fluoxetine effects on inhibitory brain act

Authors: Kaylita Chantiluke Nadia Barrett Vincent Giampietro Paramala Santosh Michael Brammer Andrew Simmons Declan G Murphy Katya Rubia

Publish Date: 2014/12/24

Volume: 232, Issue: 12, Pages: 2071-2082

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Abstract

Attention deficit hyperactivity disorder ADHD and autism spectrum disorder ASD are often comorbid and have both performance and brain dysfunctions during motor response inhibition Serotonin agonists modulate motor response inhibition and have shown positive behavioural effects in both disordersWe therefore used functional magnetic resonance imaging fMRI to investigate the so far unknown shared and disorderspecific inhibitory brain dysfunctions in these two disorders as well as the effects of a single dose of the selective serotonin reuptake inhibitor fluoxetineAgematched boys with ADHD 18 ASD 19 and healthy controls 25 were compared with fMRI during a stop task measuring motor inhibition Patients were scanned twice under either an acute dose of fluoxetine or placebo in a doubleblind placebocontrolled randomised design Repeated measures analyses within patients assessed drug effects To test for potential normalisation effects of brain dysfunctions patients under each drug condition were compared to controlsUnder placebo relative to controls ASD boys showed overactivation in left and right inferior frontal cortex IFC while ADHD boys showed disorderspecific underactivation in orbitofrontal cortex OFC and basal ganglia Under fluoxetine the prefrontal dysfunctions were no longer observed due to inverse effects of fluoxetine on these activations fluoxetine downregulated IFC and OFC activation in ASD but upregulated them in ADHDThe findings show that fluoxetine normalises frontal lobe dysfunctions in both disorders via inverse effects downregulating abnormally increased frontal activation in ASD and upregulating abnormally decreased frontal activation in ADHD potentially reflecting inverse baseline serotonin levels in both disordersAttention deficit hyperactivity disorder ADHD is a neurodevelopmental disorder defined by ageinappropriate levels of inattention impulsivity and hyperactivity American Psychiatric Association 2000 Autism spectrum disorder ASD is defined by impairments in communication social interaction and by restricted and repetitive behaviours American Psychiatric Association 2000 There is increasing evidence for comorbidity between disorders Rommelse et al 2011 Simonoff et al 2008 van der Meer et al 2012 and shared executive function deficits Corbett et al 2009 Geurts et al 2004 in particular in motor response inhibition Alderson et al 2007 Corbett et al 2009 Lipsyzc and Schachar 2010 Robinson et al 2009 albeit less consistently in ASD Ozonoff and Strayer 1997 Raymaekers et al 2007 Furthermore this has been associated with impulsiveness in ADHD and motor stereotypies in ASD Langen et al 2011 This overlap was highlighted by recent changes to the DSMV that allows codiagnosis of ADHD and ASD http//wwwdsm5org/In ADHD there is consistent evidence of underactivation compared to controls in inferior/orbitofrontal frontal cortex IFC/OFC supplementary motor area SMA and caudate/thalamus during inhibition tasks Cubillo et al 2012 Rubia 2011 Rubia et al 2014 Rubia et al 1999 Rubia et al 2005b Cortese et al 2012 Hart et al 2013 In children with ASD however no study has investigated the neurofunctional underpinnings of response inhibition In adults with ASD fMRI studies report inconsistent findings of increased activation in left IFC and decreased activation in right IFC and anterior cingulate cortex ACC during the go/nogo task Kana et al 2007 Schmitz et al 2006 Therefore a key question is whether the underlying neurobiology of shared cognitive phenotypes is shared or disorderspecific

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