Cholinergic Modulation of Disorder-Relevant Neural Circuits in Generalized Anxiety Disorder

Wise, Toby; Patrick, Fiona; Meyer, Nicholas; Mazibuko, Ndaba; Oates, Alice; Bijl, Anne H M van der; Danjou, Philippe; O’Connor, Susan; Doolin, Elizabeth; Wooldridge, Caroline; Rathjen, Deborah; Macare, Christine; Williams, Steven; Perkins, Adam; Young, Allan H.

doi:10.1016/j.biopsych.2019.12.013

Cited by 22 publications

(13 citation statements)

References 44 publications

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“…Most importantly, results show both low and high doses of the candidate anxiolytic drug BNC210 significantly reduced Flight Intensity relative to placebo, but as a ushaped relationship in which the low dose of BNC210 was most effective. This latter result echoes the findings of our recent fMRI study in this same cohort, suggesting that although it could perhaps be a cohort effect, it is not a methodological artefact, as the fMRI data showed the low dose of BNC210 was the most potent in reducing amygdala reactivity to fearful faces compared to placebo and also reduced connectivity between the amygdala and the anterior cingulate cortex 5 . In that paper we suggested that the effects of BNC210 may be explained by suppressive action on glutamatergic interneurons in the basolateral amygdala.…”

Section: Discussionsupporting

confidence: 87%

“…As mentioned above, previous published work by our team, using this same cohort, showed that the low dose of BNC210 reduces amygdala responses to fearful faces and reduces task-related anterior-cingulate functional connectivity in a sample of individuals with GAD 5 . Our behavioural and self-reported state anxiety data complement that work since amygdala hyperactivity to threatrelated stimuli reflects anxiety 31,32 , and marketed anxiolytic drugs altering the GABAergic and serotonergic systems, reduce amygdala responses to these stimuli 33,34 .…”

Section: Discussionsupporting

confidence: 57%

“…This molecule is known as BNC210 and pre-clinical work has shown it is safe, well-tolerated and non-sedating 4 . We recently found evidence from functional Magnetic Resonance Imaging (fMRI) that BNC210 engages threat-processing brain systems, as it significantly reduced amygdala reactivity to fearful faces compared to placebo in a cohort of 24 GAD patients, as well as reducing connectivity between the amygdala and the anterior cingulate cortex 5 .…”

Section: Introductionmentioning

confidence: 99%

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Cholinergic modulation of disorder-relevant human defensive behaviour in generalised anxiety disorder

et al. 2021

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Drugs that are clinically effective against anxiety disorders modulate the innate defensive behaviour of rodents, suggesting these illnesses reflect altered functioning in brain systems that process threat. This hypothesis is supported in humans by the discovery that the intensity of threat-avoidance behaviour is altered by the benzodiazepine anxiolytic lorazepam. However, these studies used healthy human participants, raising questions as to their validity in anxiety disorder patients, as well as their generalisability beyond GABAergic benzodiazepine drugs. BNC210 is a novel negative allosteric modulator of the alpha 7 nicotinic acetylcholine receptor and we recently used functional Magnetic Resonance Imaging to show it reduced amygdala responses to fearful faces in generalised anxiety disorder patients. Here we report the effect of BNC210 on the intensity of threat-avoidance behaviour in 21 female GAD patients from the same cohort. We used the Joystick Operated Runway Task as our behavioural measure, which is a computerised human translation of the Mouse Defense Test Battery, and the Spielberger state anxiety inventory as our measure of state affect. Using a repeated-measures, within-subjects design we assessed the effect of BNC210 at two dose levels versus placebo (300 mg and 2000 mg) upon two types of threat-avoidance behaviour (Flight Intensity and Risk Assessment Intensity). We also tested the effects of 1.5 mg of the benzodiazepine lorazepam as an active control. BNC210 significantly reduced Flight Intensity relative to placebo and the low dose of BNC210 also significantly reduced self-reported state anxiety. Risk Assessment Intensity was not significantly affected. Results show both human defensive behaviour and state anxiety are influenced by cholinergic neurotransmission and there provide converging evidence that this system has potential as a novel target for anxiolytic pharmacotherapy.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

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Cholinergic modulation of disorder-relevant human defensive behaviour in generalised anxiety disorder

et al. 2021

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“…PF-06372865, a GABA-A positive allosteric modulator, tested at two doses, failed to separate from placebo as an adjunctive treatment in patients with GAD ( 176 ). On an encouraging note, BNC-210 (IW-2143), an α7 nicotinic acetylcholine receptor–negative allosteric modulator which also modulates the GABA receptor, was reported to result in reduced amygdalar activation to fearful faces compared to placebo and comparably to lorazepam, in patients with GAD ( 177 ). Although it is unknown how many GABA modulators are being studied in anxiety, preclinical research suggests that several agents may be in the pipeline ( 178 ).…”

Section: Novel Treatments For Anxiety Disordersmentioning

confidence: 99%

Pharmacotherapy of Anxiety Disorders: Current and Emerging Treatment Options

et al. 2020

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Anxiety disorders are the most prevalent psychiatric disorders and a leading cause of disability. While there continues to be expansive research in posttraumatic stress disorder (PTSD), depression and schizophrenia, there is a relative dearth of novel medications under investigation for anxiety disorders. This review's first aim is to summarize current pharmacological treatments (both approved and off-label) for panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), and specific phobias (SP), including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), azapirones (e.g., buspirone), mixed antidepressants (e.g., mirtazapine), antipsychotics, antihistamines (e.g., hydroxyzine), alpha- and beta-adrenergic medications (e.g., propranolol, clonidine), and GABAergic medications (benzodiazepines, pregabalin, and gabapentin). Posttraumatic stress disorder and obsessive-compulsive disorder are excluded from this review. Second, we will review novel pharmacotherapeutic agents under investigation for the treatment of anxiety disorders in adults. The pathways and neurotransmitters reviewed include serotonergic agents, glutamate modulators, GABAergic medications, neuropeptides, neurosteroids, alpha- and beta-adrenergic agents, cannabinoids, and natural remedies. The outcome of the review reveals a lack of randomized double-blind placebo- controlled trials for anxiety disorders and few studies comparing novel treatments to existing anxiolytic agents. Although there are some recent randomized controlled trials for novel agents including neuropeptides, glutamatergic agents (such as ketamine and d-cycloserine), and cannabinoids (including cannabidiol) primarily in GAD or SAD, these trials have largely been negative, with only some promise for kava and PH94B (an inhaled neurosteroid). Overall, the progression of current and future psychopharmacology research in anxiety disorders suggests that there needs to be further expansion in research of these novel pathways and larger-scale studies of promising agents with positive results from smaller trials.

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“…PF-06372865, a GABA-A positive allosteric modulator, tested at two doses, failed to separate from placebo as an adjunctive treatment in patients with GAD (176). On an encouraging note, BNC-210 (IW-2143), an a7 nicotinic acetylcholine receptor-negative allosteric modulator which also modulates the GABA receptor, was reported to result in reduced amygdalar activation to fearful faces compared to placebo and comparably to lorazepam, in patients with GAD (177). Although it is unknown how many GABA modulators are being studied in anxiety, preclinical research suggests that several agents may be in the pipeline (178).…”

Section: Novel Treatments For Anxiety Disordersmentioning

confidence: 99%

Pharmacotherapy of Anxiety Disorders: Current and Emerging Treatment Options

Garakani¹,

Murrough²,

Freire³

et al. 2021

FOC

View full text Add to dashboard Cite

Anxiety disorders are the most prevalent psychiatric disorders and a leading cause of disability. While there continues to be expansive research in posttraumatic stress disorder (PTSD), depression and schizophrenia, there is a relative dearth of novel medications under investigation for anxiety disorders. This review's first aim is to summarize current pharmacological treatments (both approved and off-label) for panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), and specific phobias (SP), including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), azapirones (e.g., buspirone), mixed antidepressants (e.g., mirtazapine), antipsychotics, antihistamines (e.g., hydroxyzine), alpha-and beta-adrenergic medications (e.g., propranolol, clonidine), and GABAergic medications (benzodiazepines, pregabalin, and gabapentin). Posttraumatic stress disorder and obsessive-compulsive disorder are excluded from this review. Second, we will review novel pharmacotherapeutic agents under investigation for the treatment of anxiety disorders in adults. The pathways and neurotransmitters reviewed include serotonergic agents, glutamate modulators, GABAergic medications, neuropeptides, neurosteroids, alpha-and beta-adrenergic agents, cannabinoids, and natural remedies. The outcome of the review reveals a lack of randomized double-blind placebocontrolled trials for anxiety disorders and few studies comparing novel treatments to existing anxiolytic agents. Although there are some recent randomized controlled trials for novel agents including neuropeptides, glutamatergic agents (such as ketamine and d-cycloserine), and cannabinoids (including cannabidiol) primarily in GAD or SAD, these trials have largely been negative, with only some promise for kava and PH94B (an inhaled neurosteroid). Overall, the progression of current and future psychopharmacology research in anxiety disorders suggests that there needs to be further expansion in research of these novel pathways and largerscale studies of promising agents with positive results from smaller trials.

show abstract

Cholinergic Modulation of Disorder-Relevant Neural Circuits in Generalized Anxiety Disorder

Cited by 22 publications

References 44 publications

Cholinergic modulation of disorder-relevant human defensive behaviour in generalised anxiety disorder

Cholinergic modulation of disorder-relevant human defensive behaviour in generalised anxiety disorder

Pharmacotherapy of Anxiety Disorders: Current and Emerging Treatment Options

Pharmacotherapy of Anxiety Disorders: Current and Emerging Treatment Options

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