The phase 2 NORAPS trial is underway to investigate the safety and efficacy of atomoxetine, a noradrenaline reuptake inhibitor, in patients with progressive supranuclear palsy (PSP) who exhibit apathy and impulsivity. This double-blinded, randomized crossover study aims to determine if atomoxetine can improve behavioral and cognitive outcomes in this patient population, with consideration given to the baseline integrity of the locus coeruleus noradrenergic system.
The NORAPS trial, presented at the 2024 International Congress of Parkinson’s Disease and Movement Disorders, is actively recruiting participants across two trial sites, with 40 patients enrolled thus far. The study protocol involves administering 40 mg of atomoxetine in liquid form versus a matched liquid placebo. The trial aims to enroll 84 participants to achieve 80% power for primary endpoints, accounting for an anticipated 10% attrition rate. The co-primary outcomes focus on safety and efficacy, specifically evaluating changes on a challenging-behaviors subscale of the Cambridge Behavioral Inventory.
Trial Design and Exclusion Criteria
Led by Robert Durcan, PhD, from the University of Cambridge, the NORAPS trial incorporates a preliminary staging process followed by an 8-week treatment period. Participants then undergo a 2-week washout period before crossing over to the alternate treatment arm. Exclusion criteria include cardiac arrhythmias, ischemic heart disease, and current use of other noradrenergic treatments.
Noradrenaline's Role in PSP
The rationale for testing a noradrenaline reuptake inhibitor in PSP stems from previous research indicating that noradrenaline levels are altered in PSP patients compared to those with Parkinson's disease (PD). A 2020 study revealed significantly higher levels of noradrenaline in PSP patients, similar to controls, while cerebrospinal fluid (CSF) samples in PD patients showed reduced noradrenaline and its major metabolite. This suggests that PD is a multi-system disease affecting multiple endogenous pathways, while PSP may have a different noradrenergic profile.
In the 2020 study, noradrenaline axis impairments were associated with worse Neuropsychiatric Inventory (NPI) scores in PSP patients. Researchers proposed that these impairments might contribute to the unique psycho-pathological profiles observed in tauopathies like PSP, and that early alterations in noradrenaline machinery could indicate a specific risk in PSP forms characterized by a worse prognosis.
Locus Coeruleus Degeneration
Further supporting this approach, research published in Acta Neuropathologica Communications in 2020 demonstrated that degeneration and tau pathology in the locus coeruleus are related to the clinical heterogeneity of PSP. Post-mortem tissue analysis from 31 PSP patients and 6 controls revealed an average 49% reduction of pigmented neurons in PSP patients compared to controls. This neuronal loss correlated with disease severity, even after adjusting for disease duration and the interval between clinical assessment and death.
The study also quantified hyperphosphorylated tau, the number of pigmented cells indicative of noradrenergic neurons, and the percentage of pigmented neurons with tau-positive inclusions. The degree of neuronal loss was negatively associated with tau-positive inclusions, with an average of 44% of pigmented neurons displaying tau-inclusions. The observed 49% loss of pigmented neurons aligns with previous studies reporting 53% and 51% reductions of medium-to-large neurons in the locus coeruleus.
James B. Rowe, director of the Cambridge Center for Frontotemporal Dementia and Related Disorders, noted that using neuromelanin pigment to identify noradrenergic cells post-mortem supports the development of non-invasive in vivo neuroimaging markers that exploit the MRI signal linked to neuromelanin presence. He added that degeneration of the locus coeruleus may be relevant to improving stratification procedures in clinical trials and highlights the importance of considering noradrenergic restoration as a potential treatment for PSP.
