The effect of d-cycloserine on brain processing of breathlessness over pulmonary rehabilitation: an experimental medicine study

Sarah L Finnegan; Olivia K Harrison; Sara Booth; Andrea Dennis; Martyn Ezra; Catherine J Harmer; Mari Herigstad; Bryan Guillaume; Thomas E Nichols; Najib M Rahman; Andrea Reinecke; Olivier Renaud; Kyle T S Pattinson

doi:10.1183/23120541.00479-2022

The effect of d-cycloserine on brain processing of breathlessness over pulmonary rehabilitation: an experimental medicine study

ERJ Open Res. 2023 Apr 3;9(2):00479-2022. doi: 10.1183/23120541.00479-2022. eCollection 2023 Mar.

Authors

Sarah L Finnegan¹, Olivia K Harrison^{1

2

3}, Sara Booth⁴, Andrea Dennis⁵, Martyn Ezra¹, Catherine J Harmer^{6

7}, Mari Herigstad⁸, Bryan Guillaume⁹, Thomas E Nichols^{1

9}, Najib M Rahman^{10

11

12}, Andrea Reinecke^{6

7}, Olivier Renaud¹³, Kyle T S Pattinson^{1

14}

Affiliations

¹ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
² Translational Neuromodeling Unit, Institute for Biomedical Engineering, University of Zurich and ETH Zurich, Zurich, Switzerland.
³ Department of Psychology, University of Otago, Dunedin, New Zealand.
⁴ Cambridge Breathlessness Intervention Service, CUNHSFT, Cambridge, UK.
⁵ Perspectum Ltd, Oxford, UK.
⁶ Department of Psychiatry, Medical Sciences, University of Oxford, Oxford, UK.
⁷ Oxford Health NHS Foundation Trust, Warneford Hospital Oxford, Oxford, UK.
⁸ Department of Biosciences and Chemistry, Sheffield Hallam University, Sheffield, UK.
⁹ Oxford Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
¹⁰ Nuffield Department of Medicine, University of Oxford, Oxford, UK.
¹¹ Oxford NIHR Biomedical Research Centre, Oxford, UK.
¹² Oxford Chinese Academy of Medicine Institute, Oxford, UK.
¹³ Department of Psychology, University of Geneva, Geneva, Switzerland.
¹⁴ Nuffield Department of Anaesthetics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

Abstract

Research question: Pulmonary rehabilitation is the best treatment for chronic breathlessness in COPD but there remains an unmet need to improve efficacy. Pulmonary rehabilitation has strong parallels with exposure-based cognitive behavioural therapies (CBT), both clinically and in terms of brain activity patterns. The partial N-methyl-d-aspartate (NMDA)-receptor agonist d-cycloserine has shown promising results in enhancing efficacy of CBT, thus we hypothesised that it would similarly augment the effects of pulmonary rehabilitation in the brain. Positive findings would support further development in phase 3 clinical trials.

Methods: 72 participants with mild-to-moderate COPD were recruited to a double-blind pre-registered (ClinicalTrials.gov identifier: NCT01985750) experimental medicine study running parallel to a pulmonary rehabilitation course. Participants were randomised to 250 mg d-cycloserine or placebo, administered immediately prior to the first four sessions of pulmonary rehabilitation. Primary outcome measures were differences between d-cycloserine and placebo in brain activity in the anterior insula, posterior insula, anterior cingulate cortices, amygdala and hippocampus following completion of pulmonary rehabilitation. Secondary outcomes included the same measures at an intermediate time point and voxel-wise difference across wider brain regions. An exploratory analysis determined the interaction with breathlessness anxiety.

Results: No difference between d-cycloserine and placebo groups was observed across the primary or secondary outcome measures. d-cycloserine was shown instead to interact with changes in breathlessness anxiety to dampen reactivity to breathlessness cues. Questionnaire and measures of respiratory function showed no group difference. This is the first study testing brain-active drugs in pulmonary rehabilitation. Rigorous trial methodology and validated surrogate end-points maximised statistical power.

Conclusion: Although increasing evidence supports therapeutic modulation of NMDA pathways to treat symptoms, we conclude that a phase 3 clinical trial of d-cycloserine would not be worthwhile.

Associated data

ClinicalTrials.gov/NCT01985750