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Modulation of Anxiety-Relevant Neural Circuits in Generalized Anxiety Disorder: A Novel Cholinergic System Pharmacotherapy Approach.

Fiona Patrick1*, Toby Wise1, 2, Nicholas Meyer3, Ndaba Mazibuko4, Alice Oates5, Anne M. Van Der Bijl6, Philippe Danjou7, Susan M. O'Connor8, Elizabeth Doolin9, Caroline Wooldridge4, Christine Macare1, Steven C. Williams2, 4, 5, Adam Perkins1 and Allan H. Young1
  • 1 Institute of Psychiatry, Psychology & Neuroscience (IoPPN), Psychological Medicine, United Kingdom
  • 2 National Institute for Health Research, United Kingdom
  • 3 Institute of Psychiatry, Psychology & Neuroscience (IoPPN), Department of Psychosis Studies, United Kingdom
  • 4 Institute of Psychiatry, Psychology & Neuroscience (IoPPN), Department of Neuroimaging, United Kingdom
  • 5 South London and Maudsley NHS Foundation Trust, United Kingdom
  • 6 Leiden University, Faculty of Social and Behavioural Sciences, Netherlands
  • 7 Biotrial, France
  • 8 Bionomics, Neuroscience Research, Australia
  • 9 Bionomics, Clinical Development, Australia

There is robust evidence for pharmacological serotonergic and GABAergic normalisation of key amygdala-centred network reactions to threat stimuli; however, these anxiolytic medications can have problematic side effects. There has been little investigation into cholinergic systems as alternate modifiers of anxiety-related amygdala networks. The current study administered a novel α7 nicotinic acetylcholine negative allosteric modulator, BNC210, to individuals with Generalized Anxiety Disorder (GAD) prior to engagement in a series of threat-related tasks. 24 Participants completed an emotional faces task and a human translation of a rodent defence task (the Joystick Operated Runway Task, JORT) whilst in an fMRI scanner, in this four-way crossover, double-blind randomised controlled Phase 2a trial. Results demonstrated that BNC210 reduced amygdala reactivity to fearful faces relative to placebo. In addition, BNC210 reduced the intensity of avoidance behaviour, relative to placebo, in the JORT task. These results suggest that the function of anxiety-related neural circuits and anxiety-related behaviours can be altered through modulation of cholinergic neurotransmission, highlighting the potential of this system as a novel anxiolytic pharmacological approach for GAD.

References

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Keywords: generalised anxiety disorder, pharmacotherapeutics, cholinergic system, randomized controlled trial, fMRI neuroimaging, novel therapeutics

Conference: ISAD LONDON 2017: Perspectives on Mood and Anxiety Disorders: Looking to the future, London, United Kingdom, 6 Jul - 7 Jul, 2017.

Presentation Type: Oral

Topic: Novel treatments

Citation: Patrick F, Wise T, Meyer N, Mazibuko N, Oates A, Van Der Bijl AM, Danjou P, O'Connor SM, Doolin E, Wooldridge C, Macare C, Williams SC, Perkins A and Young AH (2019). Modulation of Anxiety-Relevant Neural Circuits in Generalized Anxiety Disorder: A Novel Cholinergic System Pharmacotherapy Approach.. Front. Psychiatry. Conference Abstract: ISAD LONDON 2017: Perspectives on Mood and Anxiety Disorders: Looking to the future. doi: 10.3389/conf.fpsyt.2017.48.00033

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Received: 26 May 2017; Published Online: 25 Jan 2019.

* Correspondence: Ms. Fiona Patrick, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), Psychological Medicine, London, United Kingdom, fiona.patrick@kcl.ac.uk