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

Background 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 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 (ID: NCT01985750 ) experimental medicine study running parallel to a pulmonary rehabilitation course. Participants were randomised to 250mg 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. Results No difference between D-cycloserine and placebo groups was observed across the primary or secondary outcome measures. Questionnaire and measures of respiratory function showed no group difference. Conclusions This is the first study testing brain-active drugs in pulmonary rehabilitation. Rigorous trial methodology and validated surrogate end-points maximised statistical power. 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. Key Messages What is the key question? Does the partial NMDA-receptor agonist, D-cycloserine, augment the effects of pulmonary rehabilitation on breathlessness related brain activity? What is the bottom line? Rigorous trial methodology and validated surrogate end-points revealed no effect of D-cycloserine on breathlessness related brain activity across pulmonary rehabilitation. Why read on? This study highlights both the value of functional magnetic resonance imaging in “de-risking” expensive clinical trials and provides detailed investigation of brain-targeted points for pharmacological treatments of breathlessness.