By Evelyn Ooi, MD
Assistant Professor of Clinical Neurology and Assistant Attending Neurologist, NewYork-Presbyterian/Weill Cornell Medical Center
SYNOPSIS: In this post hoc secondary analysis of a Phase II/III randomized clinical trial of davunetide for progressive supranuclear palsy (PSP), investigators found that patients with PSP prescribed benzodiazepine derivatives experienced more rapid worsening of their PSP Rating Scale scores over time.
SOURCE: Iyer JM, Gunzler D, Lang AE, et al. Concomitant medications for progressive supranuclear palsy: A secondary analysis of a randomized clinical trial. JAMA Neurol 2024; Jan 22. doi:10.1001/jamaneurol.2023.5215. [Online ahead of print].
Progressive supranuclear palsy (PSP) is a complex neurodegenerative disease marked by progressive decline in movement, gait and postural stability, eye movements, speech, and cognitive function. There are no current curative or disease modifying therapies, or U.S. Food and Drug Administration-approved therapies. Current standard-of-care management focuses on supportive and symptomatic treatment, often driven by experience and cohort studies, with a paucity of recommendations based on randomized controlled trials. Although there have been several purported disease-modifying agents tried in completed Phase II/III clinical trials, they have not shown clinical efficacy thus far.
However, important lessons still can be gleaned from such trials. In the completed Phase II/III randomized clinical trial of davunetide for PSP, which did not show treatment effect, ample data regarding patient clinical progression and medication use were collected. In a post hoc secondary analysis of this trial, the authors investigated the progression of PSP and its association with various medication classes.
Participants in the initial 52-week trial completed the PSP Rating Scale (PSPRS) at standardized time points and provided information on concomitant medication use. Initial models included all medications taken by at least 10% of participants, with the main outcome being repeated PSPRS scores. Each medication class was evaluated as a fixed effect with and without a time × medication interaction term in models using strict Bonferroni correction (cutoff, P < 0.0016). Adjustments were made for prescribing indications, baseline demographics, and disease duration and severity.
Among 305 participants (144 [47.2%] female; 161 [52.8%] male; mean [standard deviation] age at screening 67.62 [6.56] years), only one medication class — benzodiazepine derivatives — was associated with more rapid worsening of PSPRS scores after statistical correction. Plotting the difference of adjusted least-squares means of PSPRS scores between baseline and each time point indicated significant differences between participants taking benzodiazepines and those not taking them, particularly at weeks 39 and 52.
After adjusting for benzodiazepine administration indications and baseline disease severity, participants taking benzodiazepines experienced a mean worsening of 17.1 (95% confidence interval [CI], 13.30-20.83) PSPRS points per year, vs. 9.9 (95% CI, 8.55-11.23) points per year for those not taking them. Notably, the timing of benzodiazepine prescription (before or during the study) did not affect PSP progression, arguing against faster PSP progression as an underlying reason for benzodiazepine prescription.
COMMENTARY
The strengths of this study include a large cohort size of patients with PSP and well-described clinical data. However, the study had limitations as well,
including potential confounding by unmeasured variables, biases in retrospective observational analysis, and the inability to establish a causal relationship between benzodiazepine use and PSP progression. Furthermore, the study’s focus on PSP patients with classic Richardson syndrome limits its generalizability to other PSP variants. The small sample size of the benzodiazepine group and the relatively short follow-up period (52 weeks) also pose limitations.
Nevertheless, given current clinical practice in PSP management, where pharmacologic treatment often is driven by experience (anecdote) and cohort studies, this finding marks a significant contribution to the clinical management of PSP. Although low-dose benzodiazepines commonly are prescribed for PSP patients for a number of reasons (e.g., insomnia, anxiety, sleep disturbance, restless legs syndrome, depression), the findings here suggest that even low doses may contribute to an increased rate of PSP progression. This underscores the need for cautious prescribing of benzodiazepines in PSP patients and highlights the importance of further research to understand the relationship between benzodiazepines and PSP progression.
